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Early host defense against virus infections

Søren R Paludan, Thomas Pradeu, Andreas Pichlmair, K Brad Wray, Jacob

Giehm Mikkelsen, David Olagnier, Trine H Mogensen

► To cite this version:

Søren R Paludan, Thomas Pradeu, Andreas Pichlmair, K Brad Wray, Jacob Giehm Mikkelsen, et al.. Early host defense against virus infections. Cell Reports, 2024, 43 (2), pp.115070. 10.1016/j.celrep.2024.115070. hal-04838766

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Submitted on 15 Dec 2024

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Perspective

Early host defense against virus infections

Søren R. Paludan,<sup>1,2,3,*</sup> Thomas Pradeu,<sup>4,5,6</sup> Andreas Pichlmair,<sup>2,7,8</sup> K. Brad Wray,<sup>2,9,10</sup> Jacob Giehm Mikkelsen,<sup>1,2</sup>

David Olagnier,<sup>1,2</sup> and Trine H. Mogensen<sup>1,2,11</sup>

SUMMARY

Early host defense eliminates many viruses before infections are established while clearing others so they remain subclinical or cause only mild disease. The field of immunology has been shaped by broad concepts, including the pattern recognition theory that currently dominates innate immunology. Focusing on early host responses to virus infections, we analyze the literature to build a working hypothesis for the principles that govern the early line of cellular antiviral defense. Aiming to ultimately arrive at a criteria-based theory with strong explanatory power, we propose that both controlling infection and limiting inflammation are key drivers for the early cellular antiviral response. This response, which we suggest is exerted by a set of “microbe- and inflammation-restricting mechanisms,” directly restrict viral replication while also counteracting inflammation. Exploring the mechanisms and physiological importance of the early layer of cellular anti-viral defense may open further lines of research in immunology.

INTRODUCTION: EARLY CELLULAR DEFENSE AGAINST
VIRUS INFECTIONS

Living organisms are constantly exposed to viruses, as demon-
strated by the high abundance of viral genomic material in
seawater and sewage<fnref n="1" /> and even in the airways of people not ex-
hibiting disease symptoms.<fnref n="2" />,<fnref n="3" /> This suggests that our immune
system eliminates many viruses before they establish infection
or does not recognize them as threats, as they are controlled
without effects on physiological cellular functions. Indeed, the
rapid effectuation of host defenses against invading viruses at
the portals of entry or access points into organs is of central
importance for the ability of the host to successfully fight mi-
crobes and for the eventual outcome of infections.<fnref n="4" /> The impor-
tance of early host-pathogen encounters is further emphasized
by the wealth of viral mechanisms known to evade and manipu-
late host cells.<fnref n="5" />⁻<fnref n="7" /> Despite this, the early mechanisms of host de-
fenses that guard the mucosal surfaces and target organs to pre-
vent establishment of infections remain poorly explained.

Unifying concepts and theories aid progress in science. They
are a prerequisite for the forming of scientific communities,
which can be the basis for discussions, meetings, collabora-
tions, and development of ideas. Therefore, constructing the

right conceptual framework for understanding the very early
events in innate immune responses to infections may release a
scientific potential that could also lead to societal progress.
For instance, concept-driven new knowledge on the immediate
immune response to microbial challenge may advance the
development of vaccines, pan-antiviral therapies, and oncolytic
virus therapy, among others, and could also lead to identifying
novel primary immunodeficiencies and autoimmune disorders
with immediate benefit for patients.

In this perspective, we examine whether the current theories in
innate immunology can explain the early events in host defense
against virus infections. Finally, building on published data and
expanding from previous conceptual discussions by us and
others,<fnref n="4" />,<fnref n="8" />,<fnref n="9" /> we propose that the guarding of homeostasis
through the immediate restriction of viruses and limitation of
pathological inflammation plays a large role in the early line of
cellular defense against virus infections.

ARE PRRs MEDIATING THE FIRST LINE OF ANTIVIRAL
DEFENSE?

Immunology as we understand it today is based on two major
paradigms, namely the theories of clonal selection and pattern

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<footnote n="1"><sup>1</sup>Department of Biomedicine, Aarhus University, Aarhus, Denmark</footnote>

<footnote n="2"><sup>2</sup>Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark</footnote>

<footnote n="3"><sup>3</sup>Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden</footnote>

<footnote n="4"><sup>4</sup>CNRS UMR 5164 ImmunoConcept, University of Bordeaux, Bordeaux, France</footnote>

<footnote n="5"><sup>5</sup>Department of Biological and Medical Sciences, University of Bordeaux, Bordeaux, France</footnote>

<footnote n="6"><sup>6</sup>Chapman University, Orange, CA, USA</footnote>

<footnote n="7"><sup>7</sup>Technical University of Munich, School of Medicine, Institute of Virology, Munich, Germany</footnote>

<footnote n="8"><sup>8</sup>German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany</footnote>

<footnote n="9"><sup>9</sup>Centre for Science Studies, Aarhus University, Aarhus, Denmark</footnote>

<footnote n="10"><sup>10</sup>Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark</footnote>

<footnote n="11"><sup>11</sup>Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark</footnote>

<footnote>*Correspondence: srp@biomed.au.dk</footnote>

<footnote>https://doi.org/10.1016/j.celrep.2024.115070</footnote>
<figure><img src="image_4.png" /><figcaption>**Figure 1. Type I IFN activity in antiviral defense**</figcaption></figure>

Type I interferons (IFNs) are expressed by cells after sensing of viruses by PRRs. IFNs are secreted and can activate adjacent cells through the IFNAR1/2 complex to induce IFN-stimulated genes (ISGs). Many ISGs directly restrict viral replication, while others stimulate inflammation and promote lymphocyte activation and specific immunity.

recognition.¹⁰⁻¹² For the purpose of this perspective, the clonal selection theory, which seeks to explains adaptive immune responses, is not highly relevant and will not be discussed further. The pattern recognition theory states that cells are endowed with a limited number of germline-encoded pattern recognition receptors (PRRs), which bind conserved microbial and mislocated self-molecules termed pathogen-/damage-associated molecular patterns (PAMPs/DAMPs) and activate the cells expressing the PRR. Certain PRRs can also be activated upon disruption of specific cellular processes by virulence factors, so called “effector-triggered immunity.”¹³ The pattern recognition theory was proposed by Charles A. Janeway in 1989¹² and was followed by the identification of cell-associated PRRs in flies, mice, and humans.¹⁴⁻¹⁶ In this perspective, we define PRRs as germline-encoded receptors that sense PAMPs and DAMPs to instigate signaling cascades ultimately activating auto- and paracrine antimicrobial activity and most often also proinflammatory activities. This does not necessarily include all primordial PRR systems found in prokaryotes. We chose this definition since we are mainly aiming to explain early cellular antiviral defense in multicellular organisms. For the present discussion, the most important aspect of PRRs is their downstream activities.

Sensing of PAMPs and DAMPs by PRRs evokes signaling activity eventually leading to host defense but also potentially inflammatory diseases if activated excessively or over a prolonged period of time.¹⁷⁻²⁴ In the case of virus infections, PRR-driven induction of the antiviral cytokines type I interferons (IFN-Is) is

pivotal and plays an important role in early antiviral responses<sup>25-29</sup> (Figure 1). This has led to the general perception in the field of innate immunity that PRRs constitute the first line of defense against infections. However, as will be discussed below, there are key observations that do not fully fit this hypothesis.

Since the proposal of the pattern recognition theory, the concept has “drifted” so that it is now commonly stated in scientific literature that PRRs constitute the first line of defense against infections.<sup>30-38</sup> This has likely been driven by the fact that PRRs are indeed germline encoded and can directly sense microbial molecules to induce signaling and expression of anti-viral cytokines, most notably IFN-Is and a panel of antimicrobial effector activities. The idea of pattern recognition constituting the first line of host defense was not proposed by Janeway in his original essay or subsequent publications,<sup>12,39</sup> but it was developed over time by scientists who worked in the realm of the theory.<sup>30-38</sup> However, a series of data published within the past few years do not support this view of early antiviral defense. First, mouse experiments where the animals are infected at mucosal surfaces have shown that detectable IFN expression and induction of gene expression are not observed within the first day of infection,<sup>40-42</sup> and IFN deficiency does not translate to elevated virus replication until day 2 of infection.<sup>40</sup> Such data show a delayed nature of the IFN response relative to the first host-pathogen encounter. Second, strong PRR activation often involves a two-step processes,<sup>43,44</sup> as well as induced expression of PRRs or signaling proteins, and also
requires PAMP levels to be above a given threshold to induce signaling.<sup>24,45,46</sup> In the context of the early stages of a virus infection, this means that PRR activation requires the viral load to increase to a certain level to induce substantial signaling and also to be around long enough to activate significant PRR signaling after the pathway has been fully primed. Third, over the past few years, defects in genes encoding constitutive antiviral immune mechanisms acting upstream of PRRs in host defense have been identified to confer susceptibility to specific virus infections.<sup>47-52</sup> This clearly indicates a non-redundant role for constitutive immune mechanisms in antiviral defense. Fourth, several reports have now shown that defects in specific constitutive immune mechanisms lead to elevated accumulation of viral nucleic acids and associated IFN-I expression,<sup>53,54</sup> indicating host defense activities acting upstream of PRRs. Fifth, prospective studies have shown that human pathogenic respiratory viruses are frequently detected in the human airways without ongoing or subsequent development of disease.<sup>2,3</sup> This suggests that subclinical control of virus infections is highly frequent. Sixth, some cell types do not use IFNs as the major system to fight viruses. Most notably, stem cells have been reported to have particularly high basal expression of a specific set of antiviral genes and hence have a pre-set antiviral program in place.<sup>55,56</sup> Since inflammatory responses compromise the plasticity of stem cells,<sup>57</sup> this could indicate that in this biological niche, a high constitutive energy cost is beneficial to avoid the potential consequences of local inflammation. Although none of the above examples alone can make a compelling case, they collectively support the conclusion that PRRs and IFNs, and hence the pattern recognition theory, cannot be applied as a unifying and universally valid concept to explain the earliest line of cellular defense against virus infections.

## EXISTING KNOWLEDGE ON IMMEDIATE ANTIVIRAL MECHANISMS

Based on the above discussion, it can be argued that current theories in immunology fail to explain the early cellular defense against virus infections (Figure 2A). We propose that the central phenomenon in immunology that remains to be conceptualized is the following *explanandum*: how do cells and tissues exert early antiviral host defense activities without compromising physiological functions? In this work, we use “disturbance of homeostasis” as a term to describe alterations of physiological functions.

To start to approach the question posed above, we will first look into some of the biological processes and systems that have been shown to exert direct cellular antiviral activity (Figure 2B). The first category of processes is direct restriction, whereby host molecules block specific steps in the replication cycle of viruses. This category includes restriction factor proteins, antimicrobial peptides, and also specific host- or microbiota-derived metabolites. For instance, SAMHD1 depletes cells for the pool of deoxynucleoside triphosphates, hence limiting the expression of a panel of viruses with a DNA stage in their replication, such as human immunodeficiency virus (HIV)-1 or herpes simplex virus 1 (HSV-1)<sup>58-60</sup> (Table 1). In addition, several defen-

sins bind virus surface proteins and cause aggregation, as seen for influenza A virus (IAV),<sup>129</sup> whereas host metabolites can alter the cellular microenvironment or form post-translational modifications of viral proteins to impair replication.<sup>106,130</sup> The mode of “virus sensing” is not confined to a pathogen-specific molecular pattern, although this can be the case, as illustrated by TRIM5α, which senses molecular determinants on the retroviral capsid.<sup>131</sup> Some restriction factors deplete or alter central biomolecules required for virus replication in infected cells, including SAMHD1 and APOBEC3.<sup>58,59,132</sup> Yet another category of restriction factors binds to host virus-dependency factors, thus competing for interactions with proteins involved in virus replication or targeting them for proteosomal degradation. These categories are exemplified by TMEFF1 and TRIM7, respectively, both elevating the threshold for productive virus replication.<sup>62,105</sup> Interestingly, several of the virus restriction factors additionally exert antagonistic activity on PRR activation, either through a reduction of the level of PAMPs<sup>54</sup> or through blockage of PRR signaling by a specific molecular mechanism.<sup>63</sup> For instance, TRIM7 targets the adaptor protein STING from the DNA-activated cGAS-STING pathway for degradation,<sup>63</sup> while MARCH2 facilitates the degradation of NEMO, which is used in multiple PRR signaling pathways, including the RNA-sensing RIG-like receptor-MAVS pathway.<sup>74</sup>

The second category of direct antiviral mechanisms is autophagy, a process through which cells sequester cytoplasmic content in double-membrane vesicles and target them for degradation by the lysosomal pathway.<sup>133</sup> In the case of virus infections, this may be the digestion of incoming viruses or virus replication “factories.” As to how the cellular autophagy machinery senses virus infections, several possibilities exist. First, autophagy is a constitutive process in cells, and hence the basal and unspecific autophagic activity may contribute to antiviral activities in the cytoplasm. Second, cells are endowed with selective autophagy receptors, such as p62/SQSTM1, which detect ubiquitinated virions and recruit the viral cargo to the autophagosome.<sup>111,134</sup> TRIM family proteins have been suggested to be central for the sensing of a broad range of viruses, including IAV, HSV-1, and encephalomyocarditis virus and linking to the autophagy machinery.<sup>135,136</sup> Third, cellular systems to sense different forms of cellular stress, such as endoplasmic reticulum (ER) stress and metabolic alterations, have been shown to trigger autophagy,<sup>137-139</sup> although this can serve both pro- and antiviral roles. As was also observed for a panel of restriction factors, autophagy exerts negative regulation of many PRR signaling pathways.<sup>112-114</sup> This occurs through a diverse set of mechanisms. In the case of the cGAS-STING pathway, autophagy targets the adaptor protein STING for degradation, thus limiting signaling activities.<sup>112</sup> Finally, the close relation between autophagy and viruses is further emphasized by several autophagy proteins directly restricting virus replication independently of autophagy.<sup>140</sup>

A third category of antiviral mechanisms involves cell death. The death of cells deprives viruses of their ability to replicate, and cell death mechanisms can, therefore, exert antiviral activity. Data from an evolutionary broad range of species spanning from invertebrates to vertebrates and including a diverse set of viruses, such as vaccinia virus, *Drosophila* C virus, and Sindbis
A

<figure><img src="image_5.png" /><figcaption>**Figure 2. Cellular processes to interfere with viral replication**</figcaption></figure>

(A) Illustration of principle levels of host defense against virus infections. We focus on mechanisms and theory in early cellular antiviral defense.

(B) Host cells can interfere with virus infection by depleting essential biomolecules (e.g., nucleotides), modulating the accessibility of host virus-dependency factors, eliminating specific viral molecules, or responding to virus-induced cellular stress. Restriction factors, autophagy, and apoptosis represent three key categories of host cell interference with virus replication.

B

<figure><img src="image_6.png" /></figure>

cells,<sup>141-143</sup> accumulation of reactive oxygen species,<sup>144</sup> ER stress pathways in the unfolded protein response,<sup>145,146</sup> and p53-dependent apoptosis.<sup>123,147</sup> Apoptosis has long been appreciated to be a non-inflammatory form of cell death due to the rapid uptake and digestion of the apoptotic cells by macrophages, with M2 macrophages having the highest phagocytic activity.<sup>148</sup> In addition, more recent data also show that the apoptotic caspases-3 and -7 specifically block signaling from the cGAS-STING pathway following mitochondrial DNA leakage and also through mediation of activation-induced cell death.<sup>125-127</sup> In addition to the categories of early antiviral defense discussed above, other mechanisms have also been identified, including RNA interference, intracellular nucleases, and soluble lectins.<sup>149-152</sup> Although these latter mechanisms are not studied in the same detail in relation to virus infections and will not be discussed in detail here, the available data suggest both inhibition of virus replication and PRR signaling, mechanisms that are illustrated by the ability of the lectin surfactant protein D to bind and directly neutralize IAV as well as the elevated inflammation in the lungs of IAV-infected mice lacking the lectin.<sup>152</sup>

For all the antiviral systems discussed above, it is important to mention that several viral immune-evasion mecha-

nisms have been identified.<sup>5,6,153</sup> In addition, human genetics studies have demonstrated non-redundant roles for restriction factors and autophagy in the protection against severe infections.<sup>47-51</sup> Collectively, these two categories of data provide strong evidence in favor of the importance of early cellular host defense mechanisms. The above-described antiviral activities work through very diverse sets of mechanisms. However, they share the common features that they are immediately ready to act, generally do not involve signal amplification, and exert their

virus, support the conclusion that the cell death of infected cells often exerts an antiviral defense and contributes to the early containment of infections.<sup>119-124</sup> The understanding of the triggers of antiviral apoptosis remains unresolved and is complicated by the fact that both PRR-dependent and -independent mechanisms induce apoptosis during virus infections. The PRR-independent modes of induction of cell death during virus infections are within the overall category of cellular stress and include the depletion of anti-apoptotic proteins in infected
<table><caption>Table 1. Examples of MIMs and their dual control of viruses and PRR signaling</caption><thead><tr><th>Category of effector mechanism</th><th>Viruses restricted</th><th>PRR pathways controlled<sup>a</sup></th><th>Reference</th></tr></thead><tbody><tr><td><strong>Restriction</strong></td><td></td><td></td><td></td></tr><tr><td>SAMHD1<sup>b</sup></td><td>HIV-1, HSV-1, EBV, VACV, HBV</td><td>cGAS-STING, RLR-MAVS</td><td>Maelfait et al.,<sup>54</sup> Goldstone et al.,<sup>58</sup> Laguette et al.,<sup>59</sup> Hollenbaugh et al.,<sup>60</sup> Maharana et al.<sup>61</sup></td></tr><tr><td>TRIM7<sup>c</sup></td><td>CVB3, NoV</td><td>cGAS-STING, RLR-MAVS</td><td>Fan et al.,<sup>62</sup> Yang et al.,<sup>63, 65</sup> Luptak et al.<sup>64</sup></td></tr><tr><td>SLFN5<sup>b</sup></td><td>HIV-1, HSV-1</td><td>IFN signaling (STAT1)</td><td>Ding et al.,<sup>66</sup> Kim et al.,<sup>67</sup> Arslan et al.<sup>68</sup></td></tr><tr><td>Tetherin<sup>a</sup></td><td>HIV-1, VSV, HSV-1, SARS-CoV-2</td><td>RLR-MAVS</td><td>Neil et al.,<sup>69</sup> Weidner et al.,<sup>70</sup> Blondeau et al.,<sup>71</sup> Martin-Sancho et al.,<sup>72</sup> Jin et al.<sup>73</sup></td></tr><tr><td>MARCH2<sup>c</sup></td><td>HIV-1</td><td>RLR-MAVS</td><td>Chathuranga et al.,<sup>74</sup> Zhang et al.<sup>75</sup></td></tr><tr><td>MARCH8<sup>b</sup></td><td>IAV, VSV, HIV-1</td><td>cGAS-STING</td><td>Tada et al.,<sup>76</sup> Villalon-Letelier et al.,<sup>77</sup> Yang et al.<sup>78</sup></td></tr><tr><td>APOBEC3s<sup>a</sup></td><td>HIV-1, HCoV-NL63, HBV, AAV</td><td>cGAS-STING</td><td>Stavrou et al.,<sup>53</sup> Sheehyet et al.,<sup>79</sup> Milewskaet al.,<sup>80</sup> Janahi and McGarvey,<sup>81</sup> Narvaiza et al.<sup>82</sup></td></tr><tr><td>SIRT3<sup>b</sup></td><td>HCMV, AdV, IAV</td><td>NLRP3 inflammasome</td><td>Koyuncu et al.,<sup>83</sup> Liu et al.<sup>84</sup></td></tr><tr><td>TRIM28/KAP1<sup>b</sup></td><td>HIV-1, ERVs</td><td>RLR-MAVS</td><td>Allouch et al.,<sup>85</sup> Jacobs et al.,<sup>86</sup> Tie et al.<sup>87</sup></td></tr><tr><td>MORC3<sup>b</sup></td><td>ERVs, HSV-1</td><td>IFNB1 gene transcription</td><td>Groh et al.,<sup>88</sup> Sloan et al.,<sup>89</sup> Gaidt et al.<sup>90</sup></td></tr><tr><td>ZAP<sup>a</sup></td><td>SINV, HCMV, JEV, HIV-1</td><td>RLR-MAVS</td><td>Kozaki et al.,<sup>91</sup> Lin et al.,<sup>92</sup> Chiu et al.,<sup>93</sup> Zhu et al.<sup>94</sup></td></tr><tr><td>LL-37<sup>c</sup></td><td>RSV, IAV</td><td>AIM2 inflammasome; cGAS-STING</td><td>Currie et al.,<sup>95</sup> Tripathi et al.,<sup>96</sup> Dombrowski et al.,<sup>97</sup> Chiliveru et al.<sup>98</sup></td></tr><tr><td>Surfactant protein D<sup>c</sup></td><td>IAV, HIV-1, SARS-CoV-2</td><td>TLR4</td><td>Meschi et al.,<sup>99</sup> Hartshorn et al.,<sup>100</sup> Hsieh et al.,<sup>101</sup> Yamazoe et al.<sup>102</sup></td></tr><tr><td>UPF1, SMG5, SMG7 (NMD)<sup>c</sup></td><td>SFV</td><td>TNFA and IL6 mRNA stability</td><td>Balistreri et al.,<sup>103</sup> Mino et al.<sup>104</sup></td></tr><tr><td>TMEFF1</td><td>HSV-1, HSV-2</td><td>-</td><td>Chan et al.,<sup>52</sup> Dai et al.<sup>105</sup></td></tr><tr><td>Succinate</td><td>IAV</td><td>RLR-MAVS</td><td>Guillon et al.,<sup>106</sup> Xiao et al.<sup>107</sup></td></tr><tr><td>Lactate</td><td>HSV-1, HSV-2, HIV-1</td><td>RLR-MAVS</td><td>Isaacs and Xu,<sup>108</sup> Tyssen et al.,<sup>109</sup> Zhang et al.<sup>110</sup></td></tr><tr><td><strong>Autophagy</strong></td><td></td><td></td><td></td></tr><tr><td></td><td>IAV, SARS-CoV-2, SINV, PoV, HSV-2, VZV</td><td>cGAS-STING, RLR-MAVS, NLRP3 inflammasome</td><td>Hait et al.,<sup>50</sup> Brinck Andersen et al.,<sup>51</sup> Orvedahl et al.,<sup>111</sup> Prabakaran et al.,<sup>112</sup> Tal et al.,<sup>113</sup> Nakahira et al.,<sup>114</sup> Martin-Sancho et al.,<sup>115</sup> Wang et al.,<sup>116</sup> Gassen et al.,<sup>117</sup> Heinz et al.<sup>118</sup></td></tr><tr><td><strong>Cell death</strong></td><td></td><td></td><td></td></tr><tr><td>Apoptosis</td><td>VACV, DCV, SINV, IAV</td><td>cGAS-STING, RLR-MAVS</td><td>Chattopadhyay et al.,<sup>119</sup> Kerr et al.,<sup>120</sup> Nainu et al.,<sup>121,122</sup> Liu et al.,<sup>123,124</sup> Rongvaux et al.,<sup>125</sup> White et al.,<sup>126</sup> Reinert et al.,<sup>127</sup> Huang et al.<sup>128</sup></td></tr></tbody></table>

AAV, adeno-associated virus; AdV, adenovirus; AIM2, absent in melanoma; cGAS, cyclic GMP-AMP synthetase; CVB3, coxsackievirus B3; DCV, *Drosophila* C virus; EBV, Epstein-Barr virus; ERV, endogenous retrovirus; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HCoV, human coronavirus; HIV-1, human immunodeficiency virus 1; HSV, herpes simplex virus; IAV, influenza A virus; JEV, Japanese encephalitis virus; MAVS, mitochondrial antiviral-signaling protein; NLRP3, NLR family pyrin domain containing 3; NMD, nonsense-mediated decay; NoV, norovirus; PoV, poliovirus; RSV, respiratory syncytial virus; RLR, RIG-like receptor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SFV, Semliki Forest virus; SINV, Sindbis virus; STING, stimulator of interferon genes; TLR, Toll-like receptor; VACV, vaccinia virus; VSV, vesicular stomatitis virus.

antiviral activity without stimulating major inflammatory activities. In fact, several of these processes inhibit PRR activation and inflammation. Thus, the immediate antiviral response is fast, of modest potency, and non-disruptive. This response allows the elimination of modest-to-moderate immediate danger while protecting physiological activities.

## IS LIMITING INFLAMMATION AN IMPORTANT PART OF THE EARLY RESPONSE TO INFECTIONS?

It is well described that immune responses must be controlled after microbes have been eliminated in order to avoid unnecessary tissue damage and to facilitate tissue repair. This process

<footnote><sup>a</sup>Directly by inhibition of specific steps in the signaling pathways or indirectly through reduction of the level of PAMPs.</footnote>

<footnote><sup>b</sup>Significant basal gene expression and further induction by type I/III IFNs (>3-fold, Interferome.org).</footnote>

<footnote><sup>c</sup>Expression not regulated by type I/III IFNs (<3-fold, Interferome.org).</footnote>
<figure><img src="image_7.png" /><figcaption>**Figure 3.** Regulation of inflammation as an important action to avoid immunopathology</figcaption></figure>

Activation of inflammation by PRRs and antigen receptors is important to obtain effective immune responses when the fitness threat from the infection pathogen is high. However, inflammation can also cause pathology and must be tightly controlled. In the efferent phase of an immune response, this is mediated by multiple mechanisms including regulatory T cells (Tregs), interleukin 10, and a wealth of molecular negative feedback loops. It is not known how inflammation is regulated in the afferent phase, but we propose that this includes microbe- and inflammation-restricting mechanisms (MIMs).

encompasses a wealth of mechanisms, including regulatory T cells, interleukin 10, and molecular negative feedback loops<sup>154</sup> (Figure 3). The absence of these mechanisms can lead to immunopathology.<sup>155</sup> In contrast, it is much less well studied whether there are mechanisms in place imposing restriction, in the very early steps of the host interaction with microbes, on the induction of inflammatory activities, including the activation of PRRs. Inflammation is a very broad term and spans from subclinical beneficial activation of antimicrobial responses to lethal acute responses. What is important for the discussion in the present perspective is that the strong activation of acute inflammatory responses as well as prolonged low-/mid-grade activation of inflammatory responses cause pathology.

Based on several of the six points listed earlier, most notably the requirement for super-threshold levels of PAMPs for the activation of some PRRs,<sup>24,45,46</sup> there are reasons to believe that there is a fitness gain by activating PRRs in a delayed manner. This idea is further supported by the identification of specific mechanisms through which host cells limit the activation of PRRs, as exemplified by the DNA-activated cGAS-STING pathway.<sup>156,157</sup> For instance, STING is retained in the ER in an inactive state through its interaction with cholesterol, and cholesterol levels in the organelle are transiently reduced upon cGAS activation to allow STING ER-to-Golgi trafficking and activation.<sup>157</sup> Interestingly, deficiency in the gene NPC1 leads to low levels of cholesterol on the ER, and NPC1-deficient mice show constitutive activation of STING and develop neuroinflammation and disease.<sup>158</sup> These observations suggest that it is indeed

important to limit early inflammatory responses and maybe even to delay onset until the levels of microorganisms reach a threshold.

From an evolutionary standpoint, it can be asked whether limiting early innate immune responses provides fitness advantages only in higher and long-lived organisms and hence has emerged late in evolution. In this regard, it is interesting to note that the *Drosophila melanogaster* Myc protein and the catalytic peptidoglycan recognition protein exert negative regulation of the innate Imd pathway, and the absence of either leads to elevated early induction of Imd-driven gene expression and the loss of fitness in flies.<sup>159,160</sup> Collectively, these data suggest that the loss of fitness due to immunopathology caused by early, excessive activation of PRR signaling is evolutionarily conserved. This, in turn, argues that multicellular organisms harboring PRRs and inflammation-sensitive physiological systems need to balance the PRR-driven responses to the level of threat posed by the invading microorganism.<sup>161</sup> In support of this, *Drosophila* populations under strong parasite pressure have evolved to display high constitutively active humoral immune defenses.<sup>162</sup>

## GUARDING OF HOMEOSTASIS AS A BEARING PRINCIPLE IN EARLY RESPONSE TO INFECTIONS

From the discussion above, we propose that the governing principle in the very first cellular reactions to virus infections is to interfere with replication through mechanisms that do not disturb homeostasis (Figure 4A). We propose that this is exerted by the classes of mechanisms described above, which we collectively call microbe- and inflammation-restricting mechanisms (MIMs). MIMs exert antiviral activity through specific effector functions and also negatively regulate inflammatory activities. The idea of protection of homeostasis as a central principle in immune responses in general has been suggested in a previous work proposing that inflammation is a response to deviations from homeostasis.<sup>163–165</sup> A panel of MIMs are listed in Table 1, including their dual control of both virus replication and PRR signaling as discussed in the section above.

The antiviral processes described in the previous section target viral replication in the infected cells without disturbing at the organism level. For instance, when restriction factors selectively target a given step in the virus replication cycle or when the proteasome degrades a viral protein, it does not globally disturb cellular balances and in fact eliminates a factor that could. Other processes do, in addition to the blockage of virus replication, specifically support the reestablishment of the steady-state conditions. For instance, autophagy eliminates dysfunctional mitochondria and protein aggregates.<sup>133</sup> Thus, these systems reestablish physiological equilibrium. This contrasts with PRR signaling, which induces inflammation and profoundly affects numerous processes that, in many cases, disturb physiological cellular activities. For instance, inflammation alters neuronal function and brain development.<sup>166,167</sup> Inflammation also impairs tissue repair and wound healing,<sup>168,169</sup> alters the electrolyte balance,<sup>170,171</sup> and reduces body growth,<sup>172,173</sup> particularly when systemic and chronic.
<figure><img src="image_8.png" /></figure>

A

<figure><img src="image_9.png" /></figure>

B

<figure><img src="image_10.png" /></figure>

C

<figure><img src="image_11.png" /><figcaption>**Figure 4. MIMs**</figcaption></figure>

(A) Microbe- and inflammation-restricting mechanisms (MIMs) exert homeostasis-protecting activity by blocking virus replication in a non-inflammatory manner and antagonizing PRR activation and activity.

(B) Illustration of the breadth of different proposed concepts in early host defense with respect to time and spatial distribution relative to the infected cell. Cell-autonomous immunity includes host defense mechanisms requiring only the individual infected cell, at the level of sensing and execution. Intrinsic immunity involves host defense mechanisms present at steady state and able to counteract infection without the requirement for infection-induced gene expression. We previously termed these constitutive immune mechanisms. MIMs include both of the above and hence include both constitutive and induced as well as both cell-autonomous and paracrine antimicrobial mechanisms.

(C) MIMs constitute the earliest cellular defense and form a barrier for infection and excessive inflammation. Second, the PRR-driven response gets induced

We propose that a MIM should fulfill all of the following criteria.

(1) Exert antiviral activity independently of PRRs and antigen-specific receptors.

(2) Respond to the presence of specific viral or cell-status-related molecules.

(3) Eliminate virus through specific cellular effector functions that target defined structures or activities.

(4) Eliminate virus in a non-inflammatory manner and, in some cases, directly limit PRR activation.

This means that MIMs are able to exert their antiviral action independently of the two main categories of immune receptors, as well as independently of IFNs. This can include both constitutive and induced antiviral effector mechanisms. At the same time, the MIMs have molecular specificity at the levels of both sensing and eliminating infection. This makes them clearly distinct from antiviral barriers imposed by physical and chemical mechanisms. Finally, the antiviral action of MIMs is direct and not associated with a cellular program evoking inflammation. Some MIMs will even have the capacity to directly limit PRR signaling and inflammatory activities. Consequently, proper action of MIMs counteracts excessive and prolonged activation of inflammation. As an example of how virus-restricting mechanisms can be evaluated against the MIM criteria, an IFN-induced restriction factor, like IFITM3, would fulfill criteria 2, 3, and 4¹⁷⁴,¹⁷⁵ but not criterion 1 and hence could not be classified as a MIM. Likewise, physical barriers like tight junctions would fulfill criteria 1 and 4 but not 2 and 3 and therefore also could not qualify as a MIM.¹⁷⁶,¹⁷⁷ By contrast, the restriction factors SAMHD1 and TRIM7, as well as the process of autophagy, fulfill all four criteria and thus can be classified as MIMs.⁵⁰,⁵¹,⁵⁴,⁵⁸⁻⁶¹,¹¹¹⁻¹¹⁸ The same is the case for the metabolite succinate, which exerts direct antiviral activity against IAV infection independently of PRRs through a molecularly defined mechanism¹⁰⁶ and directly blocks RIG-I-like receptor (RLR)-MAVS signaling.¹⁰⁷

We would like to add a specific note to criterion 4. Intuitively, many immunologists would assume that by simply limiting infection, PRR signaling would be suppressed. While this is certainly often correct and likely to explain the regulation of PRR activation and inflammation, there are several examples of this not being the case.¹⁷⁸⁻¹⁸⁰ Moreover, a number of restriction factors and death modalities with antiviral activity amplify immune activities through different mechanisms.¹⁴²,¹⁸¹,¹⁸² Therefore, the link between a virus-restricting mechanism and inflammation is more complex than one may anticipate. On this basis, we find it worth including as a criterion for MIMs.

The power of a theoretical framework for a research field will ultimately be determined by its explanatory and predictive power. Based on the criteria above, we claim that if what we are proposing is correct, then the following predictions will also be correct.

and amplified, thus evoking more potent defense activities but also inflammation and co-stimulation of lymphocytes. Third, antigen-receptor-driven immune responses are activated with highly specific immune responses, memory, and inflammation.
(1) Action of MIMs will enable elimination of infections without causing tissue damage.

(2) Insufficient action of MIMs will impair early host defense and lead to elevated PRR-driven inflammation.

(3) MIMs eliminate endogenous DAMPs, thus preventing immunopathology during steady state and limiting inflammation during sterile tissue damage.

(4) Organs and cell types highly sensitive to immunopathology will have high activity of MIMs and rely much on these mechanisms to eliminate danger.

(5) Body surfaces frequently exposed to invading pathogens have high activity of MIMs.

(6) MIMs with dual antimicrobial and anti-inflammatory activity evolved with the emergence of PRRs and cellular immunity.

(7) The action of MIMs decreases the delivery efficiency of several treatments, including gene therapy, oncolytic viruses, and some types of vaccines.

Future studies should examine the claims listed above. For instance, individuals with defects in MIMs or individuals infected with viruses evading these mechanisms would, according to our proposal, exhibit an elevated early viral load as well as accelerated and augmented inflammatory responses driven by PRRs. This has indeed been observed in a series of studies,⁵²⁻⁵⁴,⁶²,¹⁰⁵,¹⁸³ although much remains to be done to determine the generality of this phenomenon.

## HOMEOSTASIS GUARDING IN RELATION TO PREVIOUSLY PROPOSED THEORIES

Many of the immune mechanisms that we propose to form the early cellular barrier to virus infections are constitutively active, and we have previously reviewed this class of effector molecules in host defense.⁴ Here, we have nevertheless classified the immune activities into homeostasis-guarding versus disruptive, not constitutive versus activated. Although the difference between these two ways of classification may appear marginal, we do believe it allows for the inclusion of a panel of recently discovered inducible early antiviral mechanisms, which we now know control both viral replication and early inflammation (Figure 4B). Included in the homeostasis-guarding category, but not the constitutive category, we find, for instance, virus-induced responses through stress pathways, such as nuclear factor erythroid 2-relate factor (Nrf2), bone morphogenetic protein (BMP), and hypoxia-induced factor (HIF) pathways.¹⁸⁴⁻¹⁸⁸ Similarly, the antiviral activity executed by induction of programmed cell death would not be included in the category of constitutive immune mechanisms,¹⁴² and we still do not know whether the antiviral activity of autophagy is mediated by the basal activity or the elevated autophagic response in infected cells.⁵⁰,¹¹¹ Prior to this work, several models for the first line of defense have been proposed.¹⁸⁹ This includes the concepts of intrinsic immunity and cell-autonomous host defense.⁸,⁹ Although they are both strong and with significant explanatory power, they have limitations. For instance, intrinsic immunity is very similar to the constitutive immune mechanisms described above⁴ and thus fails to include the stress-sensing antiviral

mechanisms, although there is now good evidence that they contribute to early control of infections in a non-inflammatory manner.¹²¹,¹⁸⁴,¹⁸⁵,¹⁸⁸ Regarding cell-autonomous host defense, this theory centers exclusively on the individual cell and does not include paracrine antimicrobial activities such as antimicrobial peptides or the cell-cell transfer of metabolites. Guarding of homeostasis as a unifying principle for the early cellular defense against virus infections, exerted through the action of MIMs, includes all of the above models (Figure 4C) as well as the regulation of inflammation. Thus, we are of the opinion that it will provide a superior basis for further development toward a theory for early cellular antiviral defense.

It could be argued that MIMs are already included in the immune layer often described in immunology textbooks as “chemical and enzymatic barriers” or “complement and antimicrobial peptides/proteins.” However, while this conceptual framework for antimicrobial defense has significant explanatory power mainly for bacterial infections, it only poorly explains virus infections. In particular, it does not include the initial cellular defense reactions against virus infections. It should be emphasized though that we cannot exclude that MIMs and the antimicrobial actions of extracellular proteins over time can be conceptualized under a common framework. This will require more experimental data and an intense effort in scientific theory building.

As is always the case when attempts are made to rigidly categorize biological systems, classifications are not as black and white as proposed. In fact, interactions between theories are seen broadly in immunology, as illustrated, for example, by interactions between the immune responses driven by clonal selection and pattern-recognition-activated responses due to co-stimulation driven by PRRs. As such, theories in immunology are not incommensurable because even though they focus on distinct phenomena (e.g., lymphocytic receptors versus PRRs), the degree of integration of the different immunological compartments is so strong that most of the theoretical work consists of identifying phenomena of interest (here, early cellular antiviral defense), proposing general explanatory mechanisms (here, MIMs), and finally integrating both temporally and mechanistically different local theories into a comprehensive picture of the immune response. Below, we give a couple of examples of this in relation to the framework we are proposing. First, there are clear interactions and overlaps between MIMs and PRR-driven immune responses. Second, there are overlaps in effector functions used to exert antiviral activity. An example of this is restriction factors expressed at significant basal levels but further induced upon PRR activation or cytokine stimulation.¹⁹⁰⁻¹⁹³ Third, tonic signaling by the IFN-I receptor is believed to contribute to the basal level of resistance against infections and to setting the threshold for susceptibility to infections with a panel of viruses, including West Nile virus, IAV, HSV-1, SARS-CoV-2, and others.¹⁹⁴⁻¹⁹⁸ This immunological tone may in fact be driven by constitutive low-grade PRR signaling driven by microbiota, endogenous retroviruses, or endogenous immunostimulatory RNA species.¹⁹⁵,¹⁹⁷,¹⁹⁹ Fourth, the function of a given biological process is context dependent and hence may change during the course of an infection. This is also the case for MIMs. For instance, while autophagy is both antiviral and exerts negative regulation of PRR signaling, it also promotes antigen presentation
by dendritic cells.¹³³ Likewise, while HIF1α signaling induces early antiviral activity,¹⁸⁸,²⁰⁰ it can also promote the differentiation of macrophages into proinflammatory M1 macrophages and shape the nature of the CD4⁺ T cell response.²⁰¹,²⁰² Finally, the metabo-lite succinate exerts direct restriction IAV replication but also pro-motes the aforementioned M1 macrophage differentiation.¹⁰⁶ These examples of “gray zones” for the idea we are proposing need to be explored in more detail, but it is tempting to speculate that some MIMs exert homeostasis-protecting activity in the early phases of an infection but can secondarily support disruptive im-mune mechanisms if activated over extended time periods.

## REQUIREMENTS FOR CHANGE IN EXPERIMENTAL SYSTEMS WHEN CHANGING RESEARCH FOCUS

When exploring a new scientific question with a different focus than the one it originates from, several things have to be changed in the design of studies. This includes not least the experimental model systems, as results obtained in experimental science are highly dependent on the choice of relevant experimental sys-tems. In the case of early cellular antiviral defense, there will, for instance, be a need to refine the animal infection models used. They will have to be modified to primarily use natural infection routes and, importantly, to be based on more physiologically rele-vant infection doses. In this regard, transmission models may become an important tool. Most models used today are based on high infection doses and biased toward uncovering phenom-ena in the realm of the pattern recognition and antigen receptor theories, which is not well adapted for a genuine understanding of early defenses. Second, human stem cell-derived organoid systems and *ex vivo* analysis of primary human cells will also be important to get in-depth knowledge on early virus-host interac-tions. At the level of discovery, the unbiased screening systems used will have to be designed to identify immediate host defense mechanisms. Interestingly, looking at the literature from the past 5-7 years, human genetics has proven to be the most powerful tool to uncover non-redundant immune mechanisms that seem to fall within the homeostasis-guarding hypothesis,⁴⁷⁻⁵⁰,⁵² followed by screens or systems biology approaches to identify viral immune evasions.¹⁸⁵,¹⁸⁸ We now start to see genome-wide and focused screens with viral replication as a readout also uncover-ing essential novel mechanisms fulfilling the MIM criteria.⁶²,¹⁰⁵,¹¹⁵ Finally, the exploration of MIMs should not be limited to highly pathogenic viruses. In fact, low- or non-pathogenic viruses may provide a strong discovery tool to identify cellular barriers that normally prevent these viruses from replication to high levels and cause disease. The recent identification of TMEFF1 as a neuron-specific restriction factor preventing the development of encephalitis by the common virus HSV-1 provides a good example of this.⁵²,¹⁰⁵ Exploring the explanatory power of MIMs to understand early antiviral defense will require even stronger integration between immunology, virology, and cell biology, and all this will benefit from including an evolutionary perspective.

## CONCLUDING REMARKS

The early defense against invading pathogens is of great impor-tance for the eventual outcome of infections, yet it remains

poorly explained. In this article, we argue that the pattern recog-nition theory cannot explain the early cellular defense against vi-rus infections. Rather, we propose that the earliest line of cellular defense against viruses is mediated by a diverse set of mecha-nisms, which we call MIMs and which directly interfere with virus replication without causing inflammation and in fact, in many cases, inhibit PRR signaling. We propose that this initial immune repertoire has been selected through the evolution of multi-cellular organisms for its capacity to eliminate the infectious challenge without causing immunopathology. Many MIMs are constitutively expressed, whereas others are induced in response to cellular stress.

In the concluding remarks of “Approaching the asymptote? Evolution and revolution in immunology,” Charles A. Janeway described how the humoral immunology theory became so dominant that the role for cells in immunology was ignored for a long time.¹² This was changed by the work of Landsteiner and the clonal selection theory by Burnet.¹¹,²⁰³ Later, the clonal selection theory dominated immunology so much that scientists in the field did not give much attention to immunological mech-anisms based on other principles. This again was profoundly changed by the pattern recognition theory proposing pathogen sensing by signaling germline-encoded receptors.¹² It may be time to add that the innate immunity field, which developed from the pattern recognition theory, focused so much on the non-clonal aspect and direct pathogen recognition that we have collectively tended to overlook the fact that PRR activation leads to inflammatory responses that have the potential to compromise fitness and also that PRRs are often expressed at low levels in the resting state and require amplification loops to get fully activated. We believe the early host cellular defense ac-tions to infections are an important part of the inner workings of the immune system, driven by principles that can be conceptu-alized. This seems to be an important, unexplored frontier in immunology.

## ACKNOWLEDGMENTS

This work was supported by a grant from the Danish National Research Foundation (DNRF164). The research of T.P. is funded by the Gordon and Betty Moore Foundation through grant GBMF9021.

## AUTHOR CONTRIBUTIONS

S.R.P. conceived the idea behind the article. S.R.P., A.P., J.G.M., D.O., and T.H.M. examined the literature and each contributed with essential input to the analysis of the field. S.R.P. and T.P. formulated the ideas about theory change, and K.B.W. provided input from a philosophy-of-science point of view. The idea was extensively discussed and revised by all authors. S.R.P. wrote the first draft, and all authors contributed to finalization. The revision was led by S.R.P., with input from all authors.

## DECLARATION OF INTERESTS

The authors declare no competing interests.

## REFERENCES

1. Silverman, A.I., and Boehm, A.B. (2021). Systematic Review and Meta-Analysis of the Persistence of Enveloped Viruses in Environmental
Waters and Wastewater in the Absence of Disinfectants. Environ. Sci. Technol. 55, 14480-14493. https://doi.org/10.1021/acs.est.1c03977.

2. Jansen, R.R., Wieringa, J., Koekkoek, S.M., Visser, C.E., Pajkrt, D., Molenkamp, R., de Jong, M.D., and Schinkel, J. (2011). Frequent detection of respiratory viruses without symptoms: toward defining clinically relevant cutoff values. J. Clin. Microbiol. 49, 2631-2636. https://doi.org/10.1128/JCM.02094-10.

3. Thavagnanam, S., Christie, S.N., Doherty, G.M., Coyle, P.V., Shields, M.D., and Heaney, L.G. (2010). Respiratory viral infection in lower airways of asymptomatic children. Acta Paediatr. 99, 394-398. https://doi.org/10.1111/j.1651-2227.2009.01627.x.

4. Paludan, S.R., Pradeu, T., Masters, S.L., and Mogensen, T.H. (2021). Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat. Rev. Immunol. 21, 137-150.

5. Malim, M.H., and Bieniasz, P.D. (2012). HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harb. Perspect. Med. 2, a006940. https://doi.org/10.1101/cshperspect.a006940.

6. Orvedahl, A., and Levine, B. (2008). Viral evasion of autophagy. Autophagy 4, 280-285. https://doi.org/10.4161/auto.5289.

7. Bowie, A.G., and Unterholzner, L. (2008). Viral evasion and subversion of pattern-recognition receptor signalling. Nat. Rev. Immunol. 8, 911-922.

8. Yan, N., and Chen, Z.J. (2012). Intrinsic antiviral immunity. Nat. Immunol. 13, 214-222. https://doi.org/10.1038/ni.2229.

9. Randow, F., MacMicking, J.D., and James, L.C. (2013). Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340, 701-706. https://doi.org/10.1126/science.1233028.

10. Kaufmann, S.H.E. (2019). Immunology's Coming of Age. Front. Immunol. 10, 684. https://doi.org/10.3389/fimmu.2019.00684.

11. Burnet, F.M. (1957). A modification of Jerne's theory of antibody production using the concept of clonal selection. Aust. J. Sci. 20, 67-69.

12. Janeway, C.A., Jr. (1989). Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol 54, 1-13.

13. Lopes Fischer, N., Naseer, N., Shin, S., and Brodsky, I.E. (2020). Effector-triggered immunity and pathogen sensing in metazoans. Nat. Microbiol. 5, 14-26. https://doi.org/10.1038/s41564-019-0623-2.

14. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., and Hoffmann, J.A. (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973-983.

15. Poltorak, A., He, X., Smirnova, I., Liu, M.Y., van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282, 2085-2088.

16. Medzhitov, R., Preston-Hurlburt, P., and Janeway, C.A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397. https://doi.org/10.1038/41131.

17. Takeuchi, O., Hoshino, K., and Akira, S. (2000). Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165, 5392-5396. https://doi.org/10.4049/jimmunol.165.10.5392.

18. Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K.J., et al. (2006). Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101-105.

19. Li, X.D., Wu, J., Gao, D., Wang, H., Sun, L., and Chen, Z.J. (2013). Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjusting effects. Science 341, 1390-1394. https://doi.org/10.1126/science.1244040.

20. Reinert, L.S., Lopusna, K., Winther, H., Sun, C., Thomsen, M.K., Nandakumar, R., Mogensen, T.H., Meyer, M., Vægter, C.B., Nyengaard, J.R., et al. (2016). Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defense in the CNS. Nat. Commun. 7, 13348.

21. Zhang, S.Y., Jouanguy, E., Ugolini, S., Smahi, A., Elain, G., Romero, P., Segal, D., Sancho-Shimizu, V., Lorenzo, L., Puel, A., et al. (2007). TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522-1527.

22. Liu, Y., Jesus, A.A., Marrero, B., Yang, D., Ramsey, S.E., Sanchez, G.A.M., Tenbrock, K., Wittkowski, H., Jones, O.Y., Kuehn, H.S., et al. (2014). Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507-518. https://doi.org/10.1056/NEJMoa1312625.

23. Brown, G.J., Cañete, P.F., Wang, H., Medhavy, A., Bones, J., Roco, J.A., He, Y., Qin, Y., Cappello, J., Ellyard, J.I., et al. (2022). TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349-356. https://doi.org/10.1038/s41586-022-04642-z.

24. Rice, G.I., Del Toro Duany, Y., Jenkinson, E.M., Forte, G.M., Anderson, B.H., Ariaudo, G., Bader-Meunier, B., Baildam, E.M., Battini, R., Beresford, M.W., et al. (2014). Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503-509. https://doi.org/10.1038/ng.2933.

25. Leib, D.A., Machalek, M.A., Williams, B.R., Silverman, R.H., and Virgin, H.W. (2000). Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene. Proc. Natl. Acad. Sci. USA 97, 6097-6101. https://doi.org/10.1073/pnas.100415697.

26. Muller, U., Steinhoff, U., Reis, L.F., Hemmi, S., Pavlovic, J., Zinkernagel, R.M., and Aguet, M. (1994). Functional role of type I and type II interferons in antiviral defense. Science 264, 1918-1921.

27. Leang, R.S., Wu, T.T., Hwang, S., Liang, L.T., Tong, L., Truong, J.T., and Sun, R. (2011). The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection. PLoS Pathog. 7, e1002292. https://doi.org/10.1371/journal.ppat.1002292.

28. Keller, B.C., Fredericksen, B.L., Samuel, M.A., Mock, R.E., Mason, P.W., Diamond, M.S., and Gale, M., Jr. (2006). Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence. J. Virol. 80, 9424-9434. https://doi.org/10.1128/JVI.00768-06.

29. Detje, C.N., Meyer, T., Schmidt, H., Kreuz, D., Rose, J.K., Bechmann, I., Prinz, M., and Kalinke, U. (2009). Local type I IFN receptor signaling protects against virus spread within the central nervous system. J. Immunol. 182, 2297-2304. https://doi.org/10.4049/jimmunol.0800596.

30. Labarrere, C.A., and Kassab, G.S. (2021). Pattern Recognition Proteins: First Line of Defense Against Coronaviruses. Front. Immunol. 12, 652252. https://doi.org/10.3389/fimmu.2021.652252.

31. Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801.

32. Ogura, Y., Sutterwala, F.S., and Flavell, R.A. (2006). The inflammasome: first line of the immune response to cell stress. Cell 126, 659-662. https://doi.org/10.1016/j.cell.2006.08.002.

33. Travis, J. (2009). Origins. On the origin of the immune system. Science 324, 580-582. https://doi.org/10.1126/science.324_580.

34. Gunther, J., and Seyfert, H.M. (2018). The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells. Semin. Immunopathol. 40, 555-565. https://doi.org/10.1007/s00281-018-0701-1.

35. Diamond, M.S., and Kanneganti, T.D. (2022). Innate immunity: the first line of defense against SARS-CoV-2. Nat. Immunol. 23, 165-176. https://doi.org/10.1038/s41590-021-01091-0.

36. Ahn, J., and Barber, G.N. (2019). STING signaling and host defense against microbial infection. Exp. Mol. Med. 51, 1-10. https://doi.org/10.1038/s12276-019-0333-0.

37. Linehan, E., and Fitzgerald, D.C. (2015). Ageing and the immune system: focus on macrophages. Eur. J. Microbiol. Immunol. 5, 14-24. https://doi.org/10.1556/EUJMI-D-14-00035.
38. Broz, P., Ohlson, M.B., and Monack, D.M. (2012). Innate immune response to Salmonella typhimurium, a model enteric pathogen. Gut Microb. 3, 62–70. https://doi.org/10.4161/gmic.19141.

39. Janeway, C.A., Jr., and Medzhitov, R. (2002). Innate immune recognition. Annu. Rev. Immunol. 20, 197–216.

40. Iversen, M.B., Reinert, L.S., Thomsen, M.K., Bagdonaite, I., Nandakumar, R., Cheshenko, N., Prabakaran, T., Vakhrushev, S.Y., Krzyzowska, M., Kratholm, S.K., et al. (2016). An innate antiviral pathway acting before interferons at epithelial surfaces. Nat. Immunol. 17, 150–158.

41. Uccellini, M.B., and Garcia-Sastre, A. (2018). ISRE-Reporter Mouse Reveals High Basal and Induced Type I IFN Responses in Inflammatory Monocytes. Cell Rep. 25, 2784–2796.e3. https://doi.org/10.1016/j.celrep.2018.11.030.

42. Lienenklaus, S., Cornitescu, M., Zietara, N., Łyszkiewicz, M., Gekara, N., Jablónska, J., Edenhofer, F., Rajewsky, K., Bruder, D., Hafner, M., et al. (2009). Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo. J. Immunol. 183, 3229–3236. https://doi.org/10.4049/jimmunol.0804277.

43. Marie, I., Durbin, J.E., and Levy, D.E. (1998). Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 17, 6660–6669.

44. Bauernfeind, F.G., Horvath, G., Stutz, A., Alnemri, E.S., MacDonald, K., Speert, D., Fernandes-Alnemri, T., Wu, J., Monks, B.G., Fitzgerald, K.A., et al. (2009). Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791. https://doi.org/10.4049/jimmunol.0901363.

45. Yan, N., Regalado-Magdos, A.D., Stigglbout, B., Lee-Kirsch, M.A., and Lieberman, J. (2010). The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11, 1005–1013.

46. Luecke, S., Holleufer, A., Christensen, M.H., Jønsson, K.L., Boni, G.A., Sørensen, L.K., Johannsen, M., Jakobsen, M.R., Hartmann, R., and Paludan, S.R. (2017). cGAS is activated by DNA in a length-dependent manner. EMBO Rep. 18, 1707–1715. https://doi.org/10.15252/embr.201744017.

47. Zhang, S.Y., Clark, N.E., Freije, C.A., Pauwels, E., Taggart, A.J., Okada, S., Mandel, H., Garcia, P., Ciancanelli, M.J., Biran, A., et al. (2018). Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell 172, 952–965.e18. https://doi.org/10.1016/j.cell.2018.02.019.

48. Lafaille, F.G., Harschnitz, O., Lee, Y.S., Zhang, P., Hasek, M.L., Kerner, G., Itan, Y., Ewaleifoh, O., Rapaport, F., Carlile, T.M., et al. (2019). Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nat. Med. 25, 1873–1884. https://doi.org/10.1038/s41591-019-0672-3.

49. de Jong, S.J., Créquer, A., Matos, I., Hum, D., Gunasekharan, V., Lorrenzo, L., Jabot-Hanin, F., Imahorn, E., Arias, A.A., Vahidnezhad, H., et al. (2018). The human C1B1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to beta-papillomaviruses. J. Exp. Med. 215, 2289–2310. https://doi.org/10.1084/jem.20170308.

50. Hait, A.S., Olagnier, D., Sancho-Shimizu, V., Skipper, K.A., Helleberg, M., Larsen, S.M., Bodda, C., Moldovan, L.I., Ren, F., Brinck Andersen, N.S., et al. (2020). Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. Sci. Immunol. 5, eabc2691. https://doi.org/10.1126/sciimmunolabc2691.

51. Brinck Andersen, N.S., Jorgensen, S.E., Skipper, K.A., Larsen, S.M., Heinz, J., Thomsen, M.M., Farahani, E., Cai, Y., Hait, A.S., Kay, L., et al. (2020). Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient. Autophagy 17, 1–16. https://doi.org/10.1080/15548627.2020.1831800.

52. Chan, Y.H., Liu, Z., Bastard, P., Khobrekar, N., Hutchison, K.M., Yamazaki, Y., Fan, Q., Matuozzo, D., Harschnitz, O., Kerrouche, N., et al. (2024). Human TMEFF1 is a restriction factor for herpes simplex virus in the brain. Nature 632, 390–400.

53. Stavrou, S., Blouch, K., Kotla, S., Bass, A., and Ross, S.R. (2015). Nucleic acid recognition orchestrates the anti-viral response to retroviruses. Cell Host. Microbe 17, 478–488. https://doi.org/10.1016/j.chom.2015.02.021.

54. Maelfait, J., Bridgeman, A., Benlahrech, A., Cursi, C., and Rehwinkel, J. (2016). Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1. Cell Rep. 16, 1492–1501. https://doi.org/10.1016/j.celrep.2016.07.002.

55. Wu, X., Dao Thi, V.L., Huang, Y., Billerbeck, E., Saha, D., Hoffmann, H.H., Wang, Y., Silva, L.A.V., Sarbanes, S., Sun, T., et al. (2018). Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172, 423–438.e25. https://doi.org/10.1016/j.cell.2017.11.018.

56. Poirier, E.Z., Buck, M.D., Chakravarty, P., Carvalho, J., Frederico, B., Cardoso, A., Healy, L., Ulferts, R., Beale, R., and Reis e Sousa, C. (2021). An isoform of Dicer protects mammalian stem cells against multiple RNA viruses. Science 373, 231–236. https://doi.org/10.1126/science.abg2264.

57. Michael, S., Achilleos, C., Panayiotou, T., and Strati, K. (2016). Inflammation Shapes Stem Cells and Stemness during Infection and Beyond. Front. Cell Dev. Biol. 4, 118. https://doi.org/10.3389/fcell.2016.00118.

58. Goldstone, D.C., Ennis-Adeniran, V., Hedden, J.J., Groom, H.C.T., Rice, G.I., Christodoulou, E., Walker, P.A., Kelly, G., Haire, L.F., Yap, M.W., et al. (2011). HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382. https://doi.org/10.1038/nature10623.

59. Laguette, N., Sobhian, B., Casartelli, N., Ringeward, M., Chable-Bessia, C., Ségéral, E., Yatim, A., Emiliani, S., Schwartz, O., and Benkirane, M. (2011). SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657. https://doi.org/10.1038/nature10117.

60. Hollenbaugh, J.A., Gee, P., Baker, J., Daly, M.B., Amie, S.M., Tate, J., Kasai, N., Kanemura, Y., Kim, D.H., Ward, B.M., et al. (2013). Host factor SAMHD1 restricts DNA viruses in non-dividing myeloid cells. PLoS Pathog. 9, e1003481. https://doi.org/10.1371/journal.ppat.1003481.

61. Maharana, S., Kretschmer, S., Hunger, S., Yan, X., Kuster, D., Traikov, S., Zillinger, T., Gentzel, M., Elangovan, S., Dasgupta, P., et al. (2022). SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA. Mol. Cell 82, 3712–3728.e10. https://doi.org/10.1016/j.molcel.2022.08.031.

62. Fan, W., Mar, K.B., Sari, L., Gaszek, I.K., Cheng, Q., Evers, B.M., Shelton, J.M., Wight-Carter, M., Siegwart, D.J., Lin, M.M., and Schoggins, J.W. (2021). TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity. Cell 184, 3410–3425.e17. https://doi.org/10.1016/j.cell.2021.04.047.

63. Yang, B., Liu, Y., Cui, Y., Song, D., Zhang, G., Ma, S., Liu, Y., Chen, M., Chen, F., Wang, H., and Wang, J. (2020). RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation. PLoS Pathog. 16, e1008387. https://doi.org/10.1371/journal.ppat.1008387.

64. Luptak, J., Mallery, D.L., Jahun, A.S., Albecka, A., Clift, D., Ather, O., Slodkowicz, G., Goodfellow, I., and James, L.C. (2022). TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing. Viruses 14, 1610. https://doi.org/10.3390/v14081610.

65. Yang, B., Zhang, G., Qin, X., Huang, Y., Ren, X., Sun, J., Ma, S., Liu, Y., Song, D., Liu, Y., et al. (2021). Negative Regulation of RNF90 on RNA Virus-Triggered Antiviral Immune Responses Targeting MAVS. Front. Immunol. 12, 730483. https://doi.org/10.3389/fimmu.2021.730483.

66. Ding, J., Wang, S., Wang, Z., Chen, S., Zhao, J., Solomon, M., Liu, Z., Guo, F., Ma, L., Wen, J., et al. (2022). Schlafen 5 suppresses human immunodeficiency virus type 1 transcription by commandeering cellular epigenetic machinery. Nucleic Acids Res. 50, 6137–6153. https://doi.org/10.1093/nar/gkac489.

67. Kim, E.T., Dybas, J.M., Kulej, K., Reyes, E.D., Price, A.M., Akhtar, L.N., Orr, A., Garcia, B.A., Boutell, C., and Weitzman, M.D. (2021).
Comparative proteomics identifies Schlafen 5 (SLFN5) as a herpes simplex virus restriction factor that suppresses viral transcription. Nat. Microbiol. 6, 234–245. https://doi.org/10.1038/s41564-020-00826-3.

68. Arslan, A.D., Sassano, A., Saleiro, D., Lisowski, P., Kosciuczuk, E.M., Fischietti, M., Eckerdt, F., Fish, E.N., and Platanias, L.C. (2017). Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma. Oncogene 36, 6006–6019. https://doi.org/10.1038/onc.2017.205.

69. Neil, S.J.D., Zang, T., and Bieniasz, P.D. (2008). Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430. https://doi.org/10.1038/nature06553.

70. Weidner, J.M., Jiang, D., Pan, X.B., Chang, J., Block, T.M., and Guo, J.T. (2010). Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J. Virol. 84, 12646–12657. https://doi.org/10.1128/JVI.01328-10.

71. Blondeau, C., Pelchen-Matthews, A., Mlcochova, P., Marsh, M., Milne, R.S.B., and Towers, G.J. (2013). Tetherin restricts herpes simplex virus 1 and is antagonized by glycoprotein M. J. Virol. 87, 13124–13133. https://doi.org/10.1128/JVI.02250-13.

72. Martin-Sancho, L., Lewinski, M.K., Pache, L., Stoneham, C.A., Yin, X., Becker, M.E., Pratt, D., Churas, C., Rosenthal, S.B., Liu, S., et al. (2021). Functional landscape of SARS-CoV-2 cellular restriction. Mol. Cell 81, 2656–2668.e8. https://doi.org/10.1016/j.molcel.2021.04.008.

73. Jin, S., Tian, S., Luo, M., Xie, W., Liu, T., Duan, T., Wu, Y., and Cui, J. (2017). Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells. Mol. Cell 68, 308–322.e4. https://doi.org/10.1016/j.molcel.2017.09.005.

74. Chathuranga, K., Kim, T.H., Lee, H., Park, J.S., Kim, J.H., Chathuranga, W.A.G., Ekanayaka, P., Choi, Y.J., Lee, C.H., Kim, C.J., et al. (2020). Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2. EMBO J. 39, e105139. https://doi.org/10.15252/embj.2020105139.

75. Zhang, Y., Lu, J., and Liu, X. (2018). MARCH2 is upregulated in HIV-1 infection and inhibits HIV-1 production through envelope protein translocation or degradation. Virology 518, 293–300. https://doi.org/10.1016/j.virol.2018.02.003.

76. Tada, T., Zhang, Y., Koyama, T., Tobiume, M., Tsunetsugu-Yokota, Y., Yamaoka, S., Fujita, H., and Tokunaga, K. (2015). MARCH8 inhibits HIV-1 infection by reducing virion incorporation of envelope glycoproteins. Nat. Med. 21, 1502–1507. https://doi.org/10.1038/nm.3956.

77. Villalon-Letelier, F., Brooks, A.G., Londrigan, S.L., and Reading, P.C. (2021). MARCH8 Restricts Influenza A Virus Infectivity but Does Not Downregulate Viral Glycoprotein Expression at the Surface of Infected Cells. M Bio 12, e0148421. https://doi.org/10.1128/mBio.01484-21.

78. Yang, X., Shi, C., Li, H., Shen, S., Su, C., and Yin, H. (2022). MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation. Sci. Signal. 15, eabk3067. https://doi.org/10.1126/scisignal.abk3067.

79. Sheehy, A.M., Gaddis, N.C., Choi, J.D., and Malim, M.H. (2002). Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650. https://doi.org/10.1038/nature00939.

80. Milewska, A., Kindler, E., Vkovski, P., Zeglen, S., Ochman, M., Thiel, V., Rajfur, Z., and Pyrc, K. (2018). APOBEC3-mediated restriction of RNA virus replication. Sci. Rep. 8, 5960. https://doi.org/10.1038/s41598-018-24448-2.

81. Janahi, E.M., and McGarvey, M.J. (2013). The inhibition of hepatitis B virus by APOBEC cytidine deaminases. J. Viral Hepat. 20, 821–828. https://doi.org/10.1111/jvh.12192.

82. Narvaiza, I., Linfesty, D.C., Greener, B.N., Hakata, Y., Pintel, D.J., Logue, E., Landau, N.R., and Weitzman, M.D. (2009). Deaminase-independent

inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog. 5, e1000439. https://doi.org/10.1371/journal.ppat.1000439.

83. Koyuncu, E., Budayeva, H.G., Miteva, Y.V., Ricci, D.P., Silhavy, T.J., Shenk, T., and Cristea, I.M. (2014). Sirtuins are evolutionarily conserved viral restriction factors. M Bio 5, e02249-14. https://doi.org/10.1128/mBio.02249-14.

84. Liu, P., Huang, G., Wei, T., Gao, J., Huang, C., Sun, M., Zhu, L., and Shen, W. (2018). Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. Biochim. Biophys. Acta, Mol. Basis Dis. 1864, 764–777. https://doi.org/10.1016/j.bbadis.2017.12.027.

85. Allouch, A., Di Primio, C., Alpi, E., Lusic, M., Arosio, D., Giacca, M., and Cereseto, A. (2011). The TRIM family protein KAP1 inhibits HIV-1 integration. Cell Host Microbe 9, 484–495. https://doi.org/10.1016/j.chom.2011.05.004.

86. Jacobs, F.M.J., Greenberg, D., Nguyen, N., Haeussler, M., Ewing, A.D., Katzman, S., Paten, B., Salama, S.R., and Haussler, D. (2014). An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245. https://doi.org/10.1038/nature13760.

87. Tie, C.H., Fernandes, L., Conde, L., Robbez-Masson, L., Sumner, R.P., Peacock, T., Rodriguez-Plata, M.T., Mickute, G., Gifford, R., Towers, G.J., et al. (2018). KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. EMBO Rep. 19, e45000. https://doi.org/10.15252/embr.201745000.

88. Groh, S., Milton, A.V., Marinelli, L.K., Sickinger, C.V., Russo, A., Bollig, H., de Almeida, G.P., Schmidt, A., Forné, I., Imhof, A., and Schotta, G. (2021). Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation. Nat. Commun. 12, 5996. https://doi.org/10.1038/s41467-021-26288-7.

89. Sloan, E., Orr, A., and Everett, R.D. (2016). MORC3, a Component of PML Nuclear Bodies, Has a Role in Restricting Herpes Simplex Virus 1 and Human Cytomegalovirus. J. Virol. 90, 8621–8633. https://doi.org/10.1128/JVI.00621-16.

90. Gaidt, M.M., Morrow, A., Fairgrieve, M.R., Karr, J.P., Yosef, N., and Vance, R.E. (2021). Self-guarding of MORC3 enables virulence factor-triggered immunity. Nature 600, 138–142. https://doi.org/10.1038/s41586-021-04054-5.

91. Kozaki, T., Takahama, M., Misawa, T., Matsuura, Y., Akira, S., and Sai-toh, T. (2015). Role of zinc-finger anti-viral protein in host defense against Sindbis virus. Int. Immunol. 27, 357–364. https://doi.org/10.1093/intimm/dxv010.

92. Lin, Y.T., Chiweshe, S., McCormick, D., Raper, A., Wickenhagen, A., De-Fillipis, V., Gaunt, E., Simmonds, P., Wilson, S.J., and Grey, F. (2020). Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early 1 gene. PLoS Pathog. 16, e1008844. https://doi.org/10.1371/journal.ppat.1008844.

93. Chiu, H.P., Chiu, H., Yang, C.F., Lee, Y.L., Chiu, F.L., Kuo, H.C., Lin, R.J., and Lin, Y.L. (2018). Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein. PLoS Pathog. 14, e1007166. https://doi.org/10.1371/journal.ppat.1007166.

94. Zhu, Y., Chen, G., Lv, F., Wang, X., Ji, X., Xu, Y., Sun, J., Wu, L., Zheng, Y.T., and Gao, G. (2011). Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation. Proc. Natl. Acad. Sci. USA 108, 15834–15839. https://doi.org/10.1073/pnas.1101676108.

95. Currie, S.M., Findlay, E.G., McHugh, B.J., Mackellar, A., Man, T., Macmillan, D., Wang, H., Fitch, P.M., Schwarze, J., and Davidson, D.J. (2013). The human cathelicidin LL-37 has antiviral activity against respiratory syncytial virus. PLoS One 8, e73659. https://doi.org/10.1371/journal.pone.0073659.

96. Tripathi, S., Tecle, T., Verma, A., Crouch, E., White, M., and Hartshorn, K.L. (2013). The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J. Gen. Virol. 94, 40–49. https://doi.org/10.1099/vir.0.045013-0.
97. Dombrowski, Y., Peric, M., Koglin, S., Kammerbauer, C., Göss, C., Anz, D., Simanski, M., Gläser, R., Harder, J., Hornung, V., et al. (2011). Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci. Transl. Med. 3, 82ra38. https://doi.org/10.1126/sci-translmed.3002001.

98. Chiliveru, S., Rahbek, S.H., Jensen, S.K., Jørgensen, S.E., Nissen, S.K., Christiansen, S.H., Mogensen, T.H., Jakobsen, M.R., Iversen, L., Johansen, C., and Paludan, S.R. (2014). Inflammatory cytokines break down intrinsic immunological tolerance of human primary keratinocytes to cytosolic DNA. J. Immunol. 192, 2395-2404. https://doi.org/10.4049/jimmunol.1302120.

99. Meschi, J., Crouch, E.C., Skolnik, P., Yahya, K., Holmskov, U., Leth-Larsen, R., Tornoe, I., Tecle, T., White, M.R., and Hartshorn, K.L. (2005). Surfactant protein D binds to human immunodeficiency virus (HIV) envelope protein gp120 and inhibits HIV replication. J. Gen. Virol. 86, 3097-3107. https://doi.org/10.1099/vir.0.80764-0.

100. Hartshorn, K.L., White, M.R., Tecle, T., Tornoe, I., Sorensen, G.L., Crouch, E.C., and Holmskov, U. (2007). Reduced influenza viral neutralizing activity of natural human trimers of surfactant protein D. Respir. Res. 8, 9. https://doi.org/10.1186/1465-9921-8-9.

101. Hsieh, M.H., Beirag, N., Murugaiah, V., Chou, Y.C., Kuo, W.S., Kao, H.F., Madan, T., Kishore, U., and Wang, J.Y. (2021). Human Surfactant Protein D Binds Spike Protein and Acts as an Entry Inhibitor of SARS-CoV-2 Pseudotyped Viral Particles. Front. Immunol. 12, 641360. https://doi.org/10.3389/fimmu.2021.641360.

102. Yamazoe, M., Nishitani, C., Takahashi, M., Katoh, T., Ariki, S., Shimizu, T., Mitsuzawa, H., Sawada, K., Voelker, D.R., Takahashi, H., and Kuroki, Y. (2008). Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors. J. Biol. Chem. 283, 35878-35888. https://doi.org/10.1074/jbc.M807268200.

103. Balistreri, G., Horvath, P., Schweingruber, C., Zünd, D., McInerney, G., Merits, A., Mühlemann, O., Azzalin, C., and Helenius, A. (2014). The host nonsense-mediated mRNA decay pathway restricts Mammalian RNA virus replication. Cell Host Microbe 16, 403-411. https://doi.org/10.1016/j.chom.2014.08.007.

104. Mino, T., Murakawa, Y., Fukao, A., Vandenbon, A., Wessels, H.H., Ori, D., Uehata, T., Tartey, S., Akira, S., Suzuki, Y., et al. (2015). Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell 161, 1058-1073. https://doi.org/10.1016/j.cell.2015.04.029.

105. Dai, Y., Idorn, M., Serrero, M.C., Pan, X., Thomsen, E.A., Narita, R., Maimaitili, M., Qian, X., Iversen, M.B., Reinert, L.S., et al. (2024). TMEFF1 is a neuron-specific restriction factor for herpes simplex virus. Nature 632, 383-389.

106. Guillon, A., Brea-Diakite, D., Cezard, A., Wacquiez, A., Baranek, T., Bourgeais, J., Picou, F., Vasseur, V., Meyer, L., Chevalier, C., et al. (2022). Host succinate inhibits influenza virus infection through succinylilation and nuclear retention of the viral nucleoprotein. EMBO J. 41, e108306. https://doi.org/10.15252/embj.2021108306.

107. Xiao, Y., Chen, X., Wang, Z., Quan, J., Zhao, X., Tang, H., Wu, H., Di, Q., Wu, Z., and Chen, W. (2022). Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS. Front. Immunol. 13, 816378. https://doi.org/10.3389/fimmu.2022.816378.

108. Isaacs, C.E., and Xu, W. (2013). Theaflavin-3,3'-digallate and lactic acid combinations reduce herpes simplex virus infectivity. Antimicrob. Agents Chemother. 57, 3806-3814. https://doi.org/10.1128/AAC.00659-13.

109. Tyssen, D., Wang, Y.Y., Hayward, J.A., Agius, P.A., DeLong, K., Aldunate, M., Ravel, J., Moench, T.R., Cone, R.A., and Tachedjian, G. (2018). Anti-HIV-1 Activity of Lactic Acid in Human Cervicovaginal Fluid. mSphere 3, e00055-18. https://doi.org/10.1128/mSphere.00055-18.

110. Zhang, W., Wang, G., Xu, Z.G., Tu, H., Hu, F., Dai, J., Chang, Y., Chen, Y., Lu, Y., Zeng, H., et al. (2019). Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS. Cell 178, 176-189.e15. https://doi.org/10.1016/j.cell.2019.05.003.

111. Orvedahl, A., MacPherson, S., Sumpter, R., Jr., Tallóczy, Z., Zou, Z., and Levine, B. (2010). Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7, 115-127.

112. Prabakaran, T., Bodda, C., Krapp, C., Zhang, B.C., Christensen, M.H., Sun, C., Reinert, L., Cai, Y., Jensen, S.B., Skouboe, M.K., et al. (2018). Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J. 37, e97858.

113. Tal, M.C., Sasai, M., Lee, H.K., Yordy, B., Shadel, G.S., and Iwasaki, A. (2009). Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl. Acad. Sci. USA 106, 2770-2775.

114. Nakahira, K., Haspel, J.A., Rathinam, V.A.K., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., Kim, H.P., et al. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230. https://doi.org/10.1038/ni.1980.

115. Martin-Sancho, L., Tripathi, S., Rodriguez-Frandsen, A., Pache, L., Sanchez-Aparicio, M., McGregor, M.J., Haas, K.M., Swaney, D.L., Nguyen, T.T., Mamede, J.I., et al. (2021). Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy. Nat. Microbiol. 6, 1319-1333. https://doi.org/10.1038/s41564-021-00964-2.

116. Wang, R., Zhu, Y., Ren, C., Yang, S., Tian, S., Chen, H., Jin, M., and Zhou, H. (2021). Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy 17, 496-511. https://doi.org/10.1080/15548627.2020.1725375.

117. Gassen, N.C., Papies, J., Bajaj, T., Emanuel, J., Dethloff, F., Chua, R.L., Trimpert, J., Heinemann, N., Niemeyer, C., Weege, F., et al. (2021). SARS-CoV-2-mediated dysregulation of metabolism and autophagy covers host-targeting antivirals. Nat. Commun. 12, 3818. https://doi.org/10.1038/s41467-021-24007-w.

118. Heinz, J.L., Hinke, D.M., Maimaitili, M., Wang, J., Sabli, I.K.D., Thomsen, M., Farahani, E., Ren, F., Hu, L., Zillinger, T., et al. (2024). Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells experts antiviral activity. J. Med. Virol. 96, e29690. https://doi.org/10.1002/jmv.29690.

119. Chattopadhyay, S., Yamashita, M., Zhang, Y., and Sen, G.C. (2011). The IRF-3/Bax-mediated apoptotic pathway, activated by viral cytoplasmic RNA and DNA, inhibits virus replication. J. Virol. 85, 3708-3716. https://doi.org/10.1128/JVI.02133-10.

120. Kerr, D.A., Larsen, T., Cook, S.H., Fannjiang, Y.R., Choi, E., Griffin, D.E., Hardwick, J.M., and Irani, D.N. (2002). BCL-2 and BAX protect adult mice from lethal Sindbis virus infection but do not protect spinal cord motor neurons or prevent paralysis. J. Virol. 76, 10393-10400. https://doi.org/10.1128/JVI.76.20.10393-10400.2002.

121. Nainu, F., Shiratsuchi, A., and Nakanishi, Y. (2017). Induction of Apoptosis and Subsequent Phagocytosis of Virus-Infected Cells As an Antiviral Mechanism. Front. Immunol. 8, 1220. https://doi.org/10.3389/fimmu.2017.01220.

122. Nainu, F., Tanaka, Y., Shiratsuchi, A., and Nakanishi, Y. (2015). Protection of Insects against Viral Infection by Apoptosis-Dependent Phagocytosis. J. Immunol. 195, 5696-5706. https://doi.org/10.4049/jimmunol.1500613.

123. Liu, B., Behura, S.K., Clem, R.J., Schneemann, A., Becnel, J., Severson, D.W., and Zhou, L. (2013). P53-mediated rapid induction of apoptosis conveys resistance to viral infection in Drosophila melanogaster. PLoS Pathog. 9, e1003137. https://doi.org/10.1371/journal.ppat.1003137.

124. Liu, W.H., Lin, Y.L., Wang, J.P., Liou, W., Hou, R.F., Wu, Y.C., and Liao, C.L. (2006). Restriction of vaccinia virus replication by a ced-3 and ced-4-dependent pathway in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 103, 4174-4179. https://doi.org/10.1073/pnas.0506442103.
125. Rongvaux, A., Jackson, R., Harman, C.C.D., Li, T., West, A.P., de Zoete, M.R., Wu, Y., Yordy, B., Lakhani, S.A., Kuan, C.Y., et al. (2014). Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563-1577. https://doi.org/10.1016/j.cell.2014.11.037.

126. White, M.J., McArthur, K., Metcalf, D., Lane, R.M., Cambier, J.C., Herold, M.J., van Delft, M.F., Bedoui, S., Lessene, G., Ritchie, M.E., et al. (2014). Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production. Cell 159, 1549-1562. https://doi.org/10.1016/j.cell.2014.11.036.

127. Reinert, L.S., Rashidi, A.S., Tran, D.N., Katzilkeris-Petras, G., Hvidt, A.K., Gohr, M., Fruhwürth, S., Bodda, C., Thomsen, M.K., Vendelbo, M.H., et al. (2021). Brain immune cells undergo cGAS-STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I interferon production. J. Clin. Invest. 131, e136824.

128. Huang, N., Groover, D., Damania, B., and Moody, C. (2022). Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31. Proc. Natl. Acad. Sci. USA 119, e2200206119. https://doi.org/10.1073/pnas.2200206119.

129. Doss, M., White, M.R., Tecle, T., Gantz, D., Crouch, E.C., Jung, G., Ruchala, P., Waring, A.J., Lehrer, R.I., and Hartshorn, K.L. (2009). Interactions of alpha-beta-and theta-defensins with influenza A virus and surfactant protein D. J. Immunol. 182, 7878-7887. https://doi.org/10.4049/jimmunol.0804049.

130. Ernandes, M.J., and Kagan, J.C. (2021). Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns. mBio 12, e00584-21. https://doi.org/10.1128/mBio.00584-21.

131. Stremlau, M., Perron, M., Lee, M., Li, Y., Song, B., Javanbakht, H., Diaz-Grifero, F., Anderson, D.J., Sundquist, W.I., and Sodroski, J. (2006). Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor. Proc. Natl. Acad. Sci. USA 103, 5514-5519.

132. Bishop, K.N., Holmes, R.K., Sheehy, A.M., and Malim, M.H. (2004). APOBEC-mediated editing of viral RNA. Science 305, 645. https://doi.org/10.1126/science.1100658.

133. Levine, B., and Kroemer, G. (2019). Biological Functions of Autophagy Genes: A Disease Perspective. Cell 176, 11-42. https://doi.org/10.1016/j.cell.2018.09.048.

134. Thinwa, J.W., Zou, Z., Parks, E., Sebti, S., Hui, K., Wei, Y., Goodarzi, M., Singh, V., Urquhart, G., Jewell, J.L., et al. (2024). CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses. J. Clin. Invest. 134, e168544. https://doi.org/10.1172/JCI168544.

135. Sparrer, K.M.J., Gableske, S., Zurenski, M.A., Parker, Z.M., Full, F., Baumgart, G.J., Kato, J., Pacheco-Rodriguez, G., Liang, C., Pornillos, O., et al. (2017). TRIM23 mediates virus-induced autophagy via activation of TBK1. Nat. Microbiol. 2, 1543-1557. https://doi.org/10.1038/s41564-017-0017-2.

136. Mandell, M.A., Jain, A., Arko-Mensah, J., Chauhan, S., Kimura, T., Dkins, C., Silvestri, G., Münch, J., Kirchhoff, F., Simonsen, A., et al. (2014). TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev. Cell 30, 394-409. https://doi.org/10.1016/j.devcel.2014.06.013.

137. Hou, L., Ge, X., Xin, L., Zhou, L., Guo, X., and Yang, H. (2014). Nonstructural proteins 2C and 3D are involved in autophagy as induced by the encephalomyocarditis virus. Virol. J. 11, 156. https://doi.org/10.1186/1743-422X-11-156.

138. Lee, Y.R., Kuo, S.H., Lin, C.Y., Fu, P.J., Lin, Y.S., Yeh, T.M., and Liu, H.S. (2018). Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo. Sci. Rep. 8, 489. https://doi.org/10.1038/s41598-017-18909-3.

139. Sharma, M., Bhattacharyya, S., Sharma, K.B., Chauhan, S., Asthana, S., Abdin, M.Z., Vrati, S., and Kalia, M. (2017). Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in

neuronal cells. J. Gen. Virol. 98, 1027-1039. https://doi.org/10.1099/jgv.0.000792.

140. Mauthe, M., Langereis, M., Jung, J., Zhou, X., Jones, A., Omta, W., Tooze, S.A., Stork, B., Paludan, S.R., Ahola, T., et al. (2016). An siRNA screen for ATG protein depletion reveals the extent of the unconventional functions of the autophagy proteome in virus replication. J. Cell Biol. 214, 619-635. https://doi.org/10.1083/jcb.201602046.

141. Cuconati, A., Mukherjee, C., Perez, D., and White, E. (2003). DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev. 17, 2922-2932. https://doi.org/10.1101/gad.1156903.

142. Orzalli, M.H., Prochera, A., Payne, L., Smith, A., Garlick, J.A., and Kagan, J.C. (2021). Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells. Immunity 54, 1447-1462.e5. https://doi.org/10.1016/j.immuni.2021.04.012.

143. Vandergaast, R., Schultz, K.L.W., Cerio, R.J., and Friesen, P.D. (2011). Active depletion of host cell inhibitor-of-apoptosis proteins triggers apoptosis upon baculovirus DNA replication. J. Virol. 85, 8348-8358. https://doi.org/10.1128/JVI.00667-11.

144. Holze, C., Michaudel, C., Mackowiak, C., Haas, D.A., Benda, C., Hubel, P., Pennemann, F.L., Schnepf, D., Wettmarshausen, J., Braun, M., et al. (2018). Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nat. Immunol. 19, 130-140. https://doi.org/10.1038/s41590-017-0013-y.

145. Zhang, H.M., Ye, X., Su, Y., Yuan, J., Liu, Z., Stein, D.A., and Yang, D. (2010). Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1. J. Virol. 84, 8446-8459. https://doi.org/10.1128/JVI.01416-09.

146. Medigeshi, G.R., Lancaster, A.M., Hirsch, A.J., Briese, T., Lipkin, W.I., Defilippis, V., Früh, K., Mason, P.W., Nikolich-Zugich, J., and Nelson, J.A. (2007). West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J. Virol. 81, 10849-10860.

147. Turpin, E., Luke, K., Jones, J., Tumpey, T., Konan, K., and Schultz-Cherry, S. (2005). Influenza virus infection increases p53 activity: role of p53 in cell death and viral replication. J. Virol. 79, 8802-8811. https://doi.org/10.1128/JVI.79.14.8802-8811.2005.

148. Jaggi, U., Yang, M., Matundan, H.H., Hirose, S., Shah, P.K., Sharifi, B.G., and Ghiasi, H. (2020). Increased phagocytosis in the presence of enhanced M2-like macrophage responses correlates with increased primary and latent HSV-1 infection. PLoS Pathog. 16, e1008971. https://doi.org/10.1371/journal.ppat.1008971.

149. Mourrain, P., Bélin, C., Elmayan, T., Feuerbach, F., Godon, C., Morel, J.B., Jouette, D., Lacombe, A.M., Nikic, S., Picault, N., et al. (2000). Arabidopsis SGS2 and SGS3 genes are required for posttranscriptional gene silencing and natural virus resistance. Cell 101, 533-542.

150. Lu, R., Maduro, M., Li, F., Li, H.W., Broitman-Maduro, G., Li, W.X., and Ding, S.W. (2005). Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans. Nature 436, 1040-1043. https://doi.org/10.1038/nature03870.

151. Birdwell, L.D., Zalinger, Z.B., Li, Y., Wright, P.W., Elliott, R., Rose, K.M., Silverman, R.H., and Weiss, S.R. (2016). Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on Basal Oas Gene Expression and Independent of Virus-Induced Interferon. J. Virol. 90, 3160-3172. https://doi.org/10.1128/JVI.03036-15.

152. LeVine, A.M., Whitsett, J.A., Hartshorn, K.L., Crouch, E.C., and Korfhaugen, T.R. (2001). Surfactant protein D enhances clearance of influenza A virus from the lung in vivo. J. Immunol. 167, 5868-5873. https://doi.org/10.4049/jimmunol.167.10.5868.

153. Benedict, C.A., Norris, P.S., and Ware, C.F. (2002). To kill or be killed: viral evasion of apoptosis. Nat. Immunol. 3, 1013-1018. https://doi.org/10.1038/ni1102-1013.
154. Veiga-Parga, T., Sehrawat, S., and Rouse, B.T. (2013). Role of regulatory T cells during virus infection. Immunol. Rev. 255, 182-196. https://doi.org/10.1111/imr.12085.

155. Vignali, D.A.A., Collison, L.W., and Workman, C.J. (2008). How regulatory T cells work. Nat. Rev. Immunol. 8, 523-532. https://doi.org/10.1038/nri2343.

156. Xing, J., Zhang, A., Zhang, H., Wang, J., Li, X.C., Zeng, M.S., and Zhang, Z. (2017). TRIM29 promotes DNA virus infections by inhibiting innate immune response. Nat. Commun. 8, 945. https://doi.org/10.1038/s41467-017-00101-w.

157. Zhang, B.C., Laursen, M.F., Hu, L., Hazrati, H., Narita, R., Jensen, L.S., Hansen, A.S., Huang, J., Zhang, Y., Ding, X., et al. (2024). Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. Nat. Commun. 15, 2760. https://doi.org/10.1038/s41467-024-47046-5.

158. Chu, T.T., Tu, X., Yang, K., Wu, J., Repa, J.J., and Yan, N. (2021). Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C. Nature 596, 570-575. https://doi.org/10.1038/s41586-021-03762-2.

159. Li, R., Zhou, H., Jia, C., Jin, P., and Ma, F. (2020). Drosophila Myc restores immune homeostasis of Imd pathway via activating miR-277 to inhibit imd/Tab2. PLoS Genet. 16, e1008989. https://doi.org/10.1371/journal.pgen.1008989.

160. Paredes, J.C., Welchman, D.P., Poidevin, M., and Lemaitre, B. (2011). Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35, 770-779. https://doi.org/10.1016/j.immuni.2011.09.018.

161. Aggarwal, K., and Silverman, N. (2008). Positive and negative regulation of the Drosophila immune response. BMB Rep. 41, 267-277. https://doi.org/10.5483/bmbrep.2008.41.4.267.

162. Zhou, S.O., Arunkumar, R., Irfan, A., Ding, S.D., Leitão, A.B., and Jiggins, F.M. (2024). The evolution of constitutively active humoral immune defenses in Drosophila populations under high parasite pressure. PLoS Pathog. 20, e1011729. https://doi.org/10.1371/journal.ppat.1011729.

163. Chovatiya, R., and Medzhitov, R. (2014). Stress, inflammation, and defense of homeostasis. Mol. Cell 54, 281-288. https://doi.org/10.1016/j.molcel.2014.03.030.

164. Kotas, M.E., and Medzhitov, R. (2015). Homeostasis, inflammation, and disease susceptibility. Cell 160, 816-827. https://doi.org/10.1016/j.cell.2015.02.010.

165. Meizlish, M.L., Franklin, R.A., Zhou, X., and Medzhitov, R. (2021). Tissue Homeostasis and Inflammation. Annu. Rev. Immunol. 39, 557-581. https://doi.org/10.1146/annurev-immunol-061020-053734.

166. Heneka, M.T., Kummer, M.P., and Latz, E. (2014). Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463-477. https://doi.org/10.1038/nri3705.

167. Livingston, J.H., and Crow, Y.J. (2016). Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres Syndrome and Beyond. Neuropediatrics 47, 355-360. https://doi.org/10.1055/s-0036-1592307.

168. Claes, L., Recknagel, S., and Ignatius, A. (2012). Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol. 8, 133-143. https://doi.org/10.1038/nrrheum.2012.1.

169. Major, J., Crotta, S., Llorian, M., McCabe, T.M., Gad, H.H., Priestnall, S.L., Hartmann, R., and Wack, A. (2020). Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science 369, 712-717. https://doi.org/10.1126/science.abc2061.

170. Barkas, F., Liberopoulos, E., Kei, A., and Elisaf, M. (2013). Electrolyte and acid-base disorders in inflammatory bowel disease. Ann. Gastroenterol. 26, 23-28.

171. Good, D.W., George, T., and Watts, B.A., 3rd. (2009). Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am. J. Physiol. Renal Physiol. 297, F866-F874. https://doi.org/10.1152/ajprenal.00335.2009.

172. Londhe, P., and Guttridge, D.C. (2015). Inflammation induced loss of skeletal muscle. Bone 80, 131-142. https://doi.org/10.1016/j.bone.2015.03.015.

173. Epsley, S., Tadros, S., Farid, A., Kargilis, D., Mehta, S., and Rajapakse, C.S. (2020). The Effect of Inflammation on Bone. Front. Physiol. 11, 511799. https://doi.org/10.3389/fphys.2020.511799.

174. Everitt, A.R., Clare, S., Pertel, T., John, S.P., Wash, R.S., Smith, S.E., Chin, C.R., Feeley, E.M., Sims, J.S., Adams, D.J., et al. (2012). IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519-523. https://doi.org/10.1038/nature10921.

175. Clement, M., Forbester, J.L., Marsden, M., Sabberwal, P., Sommerville, M.S., Wellington, D., Dimonte, S., Clare, S., Harcourt, K., Yin, Z., et al. (2022). IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses. Nat. Commun. 13, 5294. https://doi.org/10.1038/s41467-022-32587-4.

176. Deng, Y., Herbert, J.A., Robinson, E., Ren, L., Smyth, R.L., and Smith, C.M. (2020). Neutrophil-Airway Epithelial Interactions Result in Increased Epithelial Damage and Viral Clearance during Respiratory Syncytial Virus Infection. J. Virol. 94, e02161-19. https://doi.org/10.1128/JVI.02161-19.

177. Smallcombe, C.C., Linfield, D.T., Harford, T.J., Bokun, V., Ivanov, A.I., Piedimonte, G., and Rezaee, F. (2019). Disruption of the airway epithelial barrier in a murine model of respiratory syncytial virus infection. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L358-L368. https://doi.org/10.1152/ajplung.00345.2018.

178. Mar, K.B., Wells, A.I., Caballero Van Dyke, M.C., Lopez, A.H., Eitson, J.L., Fan, W., Hanners, N.W., Evers, B.M., Shelton, J.M., and Schoggins, J.W. (2023). LY6E is a pan-coronavirus restriction factor in the respiratory tract. Nat. Microbiol. 8, 1587-1599. https://doi.org/10.1038/s41564-023-01431-w.

179. Feng, J., Cao, Z., Wang, L., Wan, Y., Peng, N., Wang, Q., Chen, X., Zhou, Y., and Zhu, Y. (2017). Inducible GBP5 Mediates the Antiviral Response via Interferon-Related Pathways during Influenza A Virus Infection. J. Innate Immun. 9, 419-435. https://doi.org/10.1159/000460294.

180. Das Sarma, J., Burrows, A., Rayman, P., Hwang, M.H., Kundu, S., Sharma, N., Bergmann, C., and Sen, G.C. (2020). Ifit2 deficiency restricts microglial activation and leukocyte migration following murine coronavirus (m-CoV) CNS infection. PLoS Pathog. 16, e1009034. https://doi.org/10.1371/journal.ppat.1009034.

181. Zhu, J., Zhang, Y., Ghosh, A., Cuevas, R.A., Forero, A., Dhar, J., Ibsen, M.S., Schmid-Burgk, J.L., Schmidt, T., Ganapathiraju, M.K., et al. (2014). Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor. Immunity 40, 936-948. https://doi.org/10.1016/j.immuni.2014.05.007.

182. Jonsson, K.L., Laustsen, A., Krapp, C., Skipper, K.A., Thavachelvam, K., Hotter, D., Egedal, J.H., Kjolby, M., Mohammadi, P., Prabakaran, T., et al. (2017). IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nat. Commun. 8, 14391. https://doi.org/10.1038/ncomms14391.

183. Wang, Y., Sharma, P., Jefferson, M., Zhang, W., Bone, B., Kipar, A., Bitto, D., Coombes, J.L., Pearson, T., Man, A., et al. (2021). Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus. EMBO J. 40, e105543. https://doi.org/10.1525/embj.2020105543.

184. Olagnier, D., Brandtoft, A.M., Gunderstofte, C., Villadsen, N.L., Krapp, C., Thielke, A.L., Laustsen, A., Peri, S., Hansen, A.L., Bonefeld, L., et al. (2018). Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506. https://doi.org/10.1038/s41467-018-05861-7.

185. Olagnier, D., Farahani, E., Thrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M.B., et al. (2020). SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat. Commun. 11, 4938. https://doi.org/10.1038/s41467-020-18764-3.
186. Eddowes, L.A., Al-Hourani, K., Ramamurthy, N., Frankish, J., Baddock, H.T., Sandor, C., Ryan, J.D., Fusco, D.N., Arezes, J., Giannoulatou, E., et al. (2019). Antiviral activity of bone morphogenetic proteins and activins. Nat. Microbiol. 4, 339–351. https://doi.org/10.1038/s41564-018-0301-9.

187. Takabayashi, H., Shinohara, M., Mao, M., Phaosawasdi, P., El-Zaatari, M., Zhang, M., Ji, T., Eaton, K.A., Dang, D., Kao, J., and Todisco, A. (2014). Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice. Gastroenterology 147, 396–406.e7. https://doi.org/10.1053/j.gastro.2014.04.015.

188. Farahani, E., Reinert, L.S., Narita, R., Serrero, M.C., Skouboe, M.K., van der Horst, D., Assil, S., Zhang, B., Iversen, M.B., Gutierrez, E., et al. (2024). Herpes Simplex Virus disrupts the HIF transcription network to block a potent innate antiviral program. Cell Rep. 43, 113792.

189. Pradeu, T., Thomma, B.P.H.J., Girardin, S.E., and Lemaitre, B. (2024). The conceptual foundations of innate immunity: Taking stock 30 years later. Immunity 57, 613–631. https://doi.org/10.1016/j.immuni.2024.03.007.

190. Gariano, G.R., Dell'Oste, V., Bronzini, M., Gatti, D., Luganini, A., De Andrea, M., Gribaudo, G., Gariglio, M., and Landolfo, S. (2012). The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog. 8, e1002498. https://doi.org/10.1371/journal.ppat.1002498.

191. Giese, S., and Marsh, M. (2014). Tetherin can restrict cell-free and cell-cell transmission of HIV from primary macrophages to T cells. PLoS Pathog. 10, e1004189. https://doi.org/10.1371/journal.ppat.1004189.

192. Riess, M., Fuchs, N.V., Idica, A., Hamdorf, M., Flory, E., Pedersen, I.M., and König, R. (2017). Interferons Induce Expression of SAMHD1 in Monocytes through Down-regulation of miR-181a and miR-30a. J. Biol. Chem. 292, 264–277. https://doi.org/10.1074/jbc.M116.752584.

193. Pinto, R.M., Bakshi, S., Lytras, S., Zakaria, M.K., Swingler, S., Worrell, J.C., Herder, V., Hargrave, K.E., Varjak, M., Cameron-Ruiz, N., et al. (2023). BTN3A3 evasion promotes the zoonotic potential of influenza A viruses. Nature 619, 338–347. https://doi.org/10.1038/s41586-023-06261-8.

194. Schoggins, J.W., Macduff, D.A., Imanaka, N., Gainey, M.D., Shrestha, B., Eitson, J.L., Mar, K.B., Richardson, R.B., Ratushny, A.V., Litvak, V., et al. (2014). Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695. https://doi.org/10.1038/nature12862.

195. Bradley, K.C., Finsterbusch, K., Schnepf, D., Crotta, S., Llorian, M., Davidson, S., Fuchs, S.Y., Staeheli, P., and Wack, A. (2019). Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection. Cell Rep. 28, 245–256.e4. https://doi.org/10.1016/j.celrep.2019.05.105.

196. Erttmann, S.F., Swacha, P., Aung, K.M., Brindefalk, B., Jiang, H., Härtova, A., Uhlin, B.E., Wai, S.N., and Gekara, N.O. (2022). The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity 55, 847–861.e10. https://doi.org/10.1016/j.immuni.2022.04.006.

197. Lima-Junior, D.S., Krishnamurthy, S.R., Bouladoux, N., Collins, N., Han, S.J., Chen, E.Y., Constantinides, M.G., Link, V.M., Lim, A.I., Enamorado, M., et al. (2021). Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota. Cell 184, 3794–3811.e19. https://doi.org/10.1016/j.cell.2021.05.020.

198. Loske, J., Rohmel, J., Lukassen, S., Stricker, S., Magalhaes, V.G., Liebig, J., Chua, R.L., Thurmann, L., Messingschlager, M., Seegebarth, A., et al. (2021). Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat. Biotechnol. 40, 319–324. https://doi.org/10.1038/s41587-021-01037-9.

199. Dorrity, T.J., Shin, H., Wiegand, K.A., Aruda, J., Closser, M., Jung, E., Gertie, J.A., Leone, A., Polfer, R., Culbertson, B., et al. (2023). Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation. Sci. Immunol. 8, eadg2979. https://doi.org/10.1126/sciimmunol.adg2979.

200. Zhao, C., Chen, J., Cheng, L., Xu, K., Yang, Y., and Su, X. (2020). Deficiency of HIF-1alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells. Emerg. Microbes Infect. 9, 691–706. https://doi.org/10.1080/22221751.2020.1742585.

201. Wang, T., Liu, H., Lian, G., Zhang, S.Y., Wang, X., and Jiang, C. (2017). HIF1alpha-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages. Mediators Inflamm. 2017, 9029327. https://doi.org/10.1155/2017/9029327.

202. Cho, S.H., Raybuck, A.L., Blagih, J., Kemboi, E., Haase, V.H., Jones, R.G., and Boothby, M.R. (2019). Hypoxia-inducible factors in CD4(+) T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity. Proc. Natl. Acad. Sci. USA 116, 8975–8984. https://doi.org/10.1073/pnas.1811702116.

203. Landsteiner, K., and Chase, M.W. (1942). Experiments on Transfer of cutaneous sensitivity to simple compounds. Exp. Biol. Med. (Maywood). 49, 688–690.