# The liver as a potential gate to the brain for encephalitic viruses

Alexandre Lalande, Lola Canus, Amélie Bourgeais, Cyrille Mathieu, Eva Ogire

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Alexandre Lalande, Lola Canus, Amélie Bourgeais, Cyrille Mathieu, Eva Ogire. The liver as a potential gate to the brain for encephalitic viruses. Current Opinion in Virology, 2025, 71, pp.101463. 10.1016/j.coviro.2025.101463. hal-05378959

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Review

# The liver as a potential gate to the brain for encephalitic viruses☆

Alexandre Lalande*, Lola Canus*, Amélie Bourgeais, Cyrille Mathieu and Eva Ogire

<figure><img src="image_2.png" /></figure>

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To model infection of viruses targeting the liver and the central nervous system, two-dimensional *in vitro* cultures rapidly show their limitations. Conversely, *in vivo* models do not easily allow the investigation of early events of the infection process. In between, *ex vivo* models, comprising mainly organoids and organotypic cultures, mimic or retain the cytoarchitecture of the organ while being relatively simple to handle and analyze. Here, we summarize the main features of brain and liver *ex vivo* models and pinpoint examples of their utilization for studying encephalitogenic and hepatotropic viruses. We highlight a gap of development and application of liver compared to *ex vivo* models in virology. Many hepatotropic viruses can also infect and/or have impacts on the central nervous system. In this sense, we sought to present these *ex vivo* models while providing a conceptual framework for the modeling of the hepatocerebral axis in the context of viral infections.

**Address**

CIRI, Centre International de Recherche en Infectiologie, Neurolnvasion TROpism and VIRal Encephalitis Team, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France

Corresponding author: Ogire, Eva (eva.ogire@inserm.fr).

*These authors contributed equally to this work.

**Current Opinion in Virology** 2025, **71**:101463

This review comes from a themed issue on **Ex-vivo models for virus research**

Edited by **Cyrille Mathieu** and **Bertrand Pain**

For complete overview about the section, refer "Ex-vivo models for virus research (2024)"

Available online 9 May 2025

https://doi.org/10.1016/j.coviro.2025.101463

1879-6257/© 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

**Introduction**

*Ex vivo* models are used to study a myriad of encephalitogenic viruses such as Borna disease virus (BDV, *Bornaviridae* family), West Nile, Japanese encephalitis and Zika viruses (WNV, JEV, ZIKV, *Flaviviridae* family), and measles, Hendra and Nipah viruses (MeV, HeV, NiV, *Paramyxoviridae* family). Encephalitis is classically defined as the inflammation of the central nervous system (CNS), resulting from the direct infection of the CNS or from peripheral events such as peripheral immune response. Many viruses reach the CNS, either accidentally or as a result of true neurotropism, transiently/acutely or chronically/persistently [1,2]. However, knowledge about these viral infections is mainly restricted to data obtained in animals or human postmortem. Thus, early stages of viral infection and related encephalitis are poorly documented, as well as is the progression of encephalitis at cellular and molecular scales in organs.

Currently, infection with hepatotropic viruses remains a major public health problem. Hepatitis A, B, C, D, and E viruses (HAV, HBV, HCV, HDV, and HEV) are considered 'exclusively' hepatotropic viruses known for causing hepatitis [3]. Other viruses can also cause hepatitis such as Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus (CCHFV, RVFV, *Bunyaviridae* family), Ebola virus (EBOV, *Filoviridae* family), or Yellow fever virus and Dengue virus (YFV, DENV, *Flaviviridae* family). Viral hepatitis is characterized by liver inflammation leading to cellular and tissular destruction, with potential consequences, including acute or chronic infections. To date, very few *ex vivo* models have been used to study hepatotropic viral infections (Figure 1).

The recent development of brain and liver *ex vivo* models offers new perspectives with better modeling of the complexity of organs, of early stages of infection, compliance with the 3Rs (Replace, Reduce, and Refine),

<footnote>* Given the role as Guest Editor, Cyrille Mathieu had no involvement in the peer review of the article and has no access to information regarding its peer-review. Full responsibility for the editorial process of this article was delegated to Bertrand Pain.</footnote>
<figure><img src="image_3.png" /><figcaption>Figure 1</figcaption></figure>

A brief history of brain and liver *ex vivo* models used for viral infection characterization. A timeline of studies first used *ex vivo* brain and liver models in the context of viral infection. Created in BioRender. MATHIEU, C. (2024) [BioRender.com/i85a633](http://BioRender.com/i85a633).

and in the screening and (pre)validation of antivirals. Currently, the hepatocerebral axis is poorly studied in the context of encephalitogenic viral infections. This mini-review describes the main existing *ex vivo* models of brain and liver used for studying viral infections, which can be useful to emulate the hepatocerebral axis.

**Ex vivo models in the study of cerebral viral infections**

Access to the brain is difficult. Complex models to appropriately investigate viral infections are thus needed. The main *ex vivo* CNS models consist of brain organoids and organotypic cultures.

**Organoids models**

Brain organoids are generated from induced pluripotent stem cells (iPSCs) and composed of neuronal and glial

cells recapitulating aspects of the brain [4]. They can be obtained from human and animal cells, which is advantageous for studying neurotropic viruses from different host species [5]. Unguided protocols produce organoids with heterogeneous structures, while guided protocols use specific patterning and growth factors to generate more organized organoids representative of a given brain region [4,6]. They allow assessing neural permissiveness, cell-to-cell, viral spread, cytopathic effects, impacts on organoid gene expression, organization, size and innate immune response upon infection, and drug testing [4,7]. Cerebral organoids have notably been used to study ZIKV-induced microcephaly and shown reduced size of organoids and disorganization upon infection [8]. Organoid growth impairment was specific to ZIKV since infection with DENV2, another closely related *Orthoflavivirus*, did not impact organoid size [8].
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) neurotropism was assessed in human brain organoids with evidence of neuronal death and perturbations of synaptic functions [9–11].

One of the usually reported limitations of such models is the lack of several cell populations such as true microglia [4] currently mimicked by adding immortalized/primary microglia or macrophage progenitors to organoids [12,13]. Nevertheless, cells with typical features of microglia can intrinsically develop in human brain organoids, disproving the consensus to date [14,15]. While lacking in the first, protocols to induce oligodendrogenesis and myelination were also reported in recent years [16]. As neural cultures, organoids mostly lack internal vasculature, blood-brain barrier (BBB), choroid plexus, and immune cells. Overall, the protocols for organoid generation are quite heterogeneous, leading to high variability, which makes comparisons difficult between studies.

## Organotypic culture models

Developed several decades ago [17], organotypic brain cultures (OBCs) are even more complex physiological models. They consist of slices of brain substructures maintained in liquid culture or on semiporous membrane. In such air-liquid interface, cultures receive nutrients from the medium beneath the membrane and oxygen from the upper side [17,18]. OBCs mainly retain the original cytoarchitecture and all the neural cell types and can be obtained from any animal model (rodents, ferrets, dogs, primates, etc.) or even human.

Examination of BDV pathogenesis in newborn rat hippocampal slice cultures has revealed a selective neuronal loss of dentate granule cells upon infection as observed *in vivo* [19]. OBC can also be used to compare different substructures in terms of intrinsic response to infection and to factors like cytokines in the absence of a circulating immune system. OBC are particularly suitable for studying initial viral neurotropism, both at the cellular and brain region scales, as reported for herpes simplex virus type 1 (HSV-1) in neonate mouse and rat OBC [20].

Age of the animal impacts their susceptibility, with infection of adult OBC being usually less extensive than that of neonate animal. Recently, human fetal OBC was developed to investigate HSV infection in a more physiological system and demonstrated a consistent cell tropism and neuropathology compared to what is observed in neonatal cases of HSV encephalitis [21]. The initial most susceptible cells of MeV infection in human CNS remained elusive, and several studies addressed this knowledge gap using OBC [18,22]. Comparison of MeV and Canine Distemper Virus early tropism and neurovirulence in olfactory bulb, hippocampal, and

cortical organotypic cultures from susceptible hosts showed high similarities of infection with these two viruses [23]. In murine OBC, ZIKV preferentially targets neocortical proliferative and developing midbrain areas and impairs neuronal migration [24], while WNV infects neurons and astrocytes, but not microglia. Microglia and astrocyte activation restrains WNV infection, with depletion of microglia in OBC promoting viral growth and cell death [25–27]. Key aspects of SARS-CoV-2 neuropathogenesis were effectively modeled in OBC, which turned out to be a choice model for rapid knowledge gathering. This virus infected and disseminated in hamster brainstem and cerebellar organotypic cultures by targeting mainly granular and Golgi neurons and induced apoptotic, necroptotic, and pyroptotic signatures [11,28]. In rat OBC, RVFV directly infected neurons, induced microglia and astrocyte activation, and caused apoptosis [29].

OBCs are useful tools for establishing proof of concept and screening antiviral molecules and have the advantage of being more predictive of *in vivo* efficiency and toxicity than 2D cell cultures [18,30,31]. However, like organoids, OBCs lack bloodstream and circulating immune system (Figure 2).

## Ex vivo models in the study of liver viral infections

The liver maintains homeostasis through its functions of storage (minerals, vitamins, glucose), metabolic detoxification (alcohol, drugs), and metabolism of nutrients (carbohydrates, fats, and proteins). The liver also participates in defenses with immunological properties through synthesized proteins (e.g. complement proteins) and resident cells (Kupffer cells) involved in innate and adaptive immunity [32,33]. The liver is an essential organ centralizing many functions supported by its different cell types (hepatocytes, cholangiocytes, stellate cells, Kupffer cells, and hepatic sinusoidal endothelial cells). Due to its detoxifying and metabolizing action, *ex vivo* liver models are more widely used in pharmacology and toxicology research [34–36], but their use in the context of infectious diseases is increasing.

## Organoid models

Hepatic organoids are 3D structures that can be obtained by deriving and differentiating iPSCs, embryonic or adult stem cells, to obtain multiple cell types composing the liver, with mainly hepatocytes and cholangiocytes.

Liver organoids show permissiveness to HCV, HBV, and HEV, with an efficient viral replication and particle secretion [37–40]. Liver organoids derived from liver stem cells can be obtained from HCV-positive patients. Interestingly, these organoids retained the ability to maintain HCV infection. Transcription reprogramming may be observed in HCV-positive organoids, leading to
<figure><img src="image_4.png" /><figcaption>Figure 2</figcaption></figure>

Advantages and drawbacks of brain organoids and organotypic culture models in virology studies. 3Rs: Replace, Reduce, Refine. Created in BioRender. MATHIEU, C. (2024) [BioRender.com/q73q002](https://BioRender.com/q73q002).

cancer development and impaired immune responses. This promising model could help to understand HCV hepatitis progression toward associated hepatocarcinoma. As for brain organoids, the absence of resident or circulating immune cells remains a challenge in understanding viral pathogenesis. In this sense, a microfluidic co-culture model of hepatic organoid and CD8+ T cells has been developed to study dynamics of adaptive immune responses to HCV [41].

For liver-targeting viruses such as DENV, YFV, RVFV, or EBOV causing acute hepatitis, liver organoids have not been exploited yet. In contrast, the hepatotropism of the SARS-CoV-2 virus has been explored through hepatic organoids that demonstrated high permissiveness and efficient replication in cholangiocytes [42–44]. Hepatic organoids models represent an interesting platform for screening and validating antivirals against hepatotropic and other viral infections.

### Organotypic culture models

Again, the current stage of research on organotypic liver cultures (OLiCs) is deficient compared to the brain. Liver sections (human, mouse, rat) are relevant for studying drug toxicology [36,45,46]. A human model referred to as precision-cut liver slice has been generated using molten agarose to maintain the structure of the liver, followed by slicing using a vibratome. The slices are then maintained in liquid culture for at least 21 days or on an air-liquid interface system for about 10 days. They also support HCV infection [47–50]. To date, this

model has been poorly used for studying viral infections, particularly at the level of host-pathogen interaction with other hepatotropic viruses. OLiCs represent a promising model with structural advantages as well as the conservation of numerous markers characteristic of the liver, such as albumin (synthesis function), hepatocyte nuclear factor 1β and 4α (markers of maintenance of hepatocyte differentiation), and cytochrome P450 enzymes (alcohol metabolism), providing a relevant *ex vivo* liver microenvironment. This *ex vivo* model allows studying the early stages of hepatotropic viral infection and testing antivirals at least during acute infection in a relevant pharmacotoxicological model. Recently, hamster OLiCs were successfully developed for the study of DENV infection and the assessment of antiviral drugs [51].

In addition, cellular metabolism was shown to modulate immunity during viral infection in the liver [52,53]. Thus, the use of OLiC would help in studying the role of activated immune cells and metabolism during infection by hepatotropic viruses. The development and maintenance of *ex vivo* liver models are still in their infancy and therefore remain a major challenge for modeling infections in the short and long term (Figure 3).

### Hepatocerebral communication axis during viral infection

The brain and liver are highly targeted by various viruses. However, very few are reported to target both organs and replicate efficiently, often due to limited
<figure><img src="image_5.png" /><figcaption>Figure 3</figcaption></figure>

Advantages and drawbacks of liver organoids and organotypic culture models in virology studies. 3Rs: Replace, Reduce, Refine. Created in BioRender. MATHIEU, C. (2024) [BioRender.com/e91p884](http://BioRender.com/e91p884).

investigation into tissues not directly involved in the final disease (neurological or hepatic). Whether some viruses may acquire properties in the liver to invade the CNS or to trigger hepatic responses responsible for the encephalitis remains poorly investigated. The study of these viral infections in *ex vivo* models is on the rise, improving the understanding of the individual pathogenesis that occurs in each organ separately.

For numerous viruses, infection usually starts with a peripheral primo tropism. This is notably the case for hepatotropic viruses, such as CCHFV [54,55], DENV [56,57], YFV [58,59], RVFV [29,60,61], that can cause neurological damage to the CNS, including meningitis, encephalitis, or encephalopathy or to the peripheral nervous system with myelitis, sensory, and peripheral neuropathies in humans [62,63]. For some of them, like RVFV, the prevention of hepatitis often leads to encephalitis, as reported in mice [64]. As for mouse hepatitis virus in mice [65], viruses can firstly infect liver either invading the brain or provoking encephalitis. While often observed for animal, this remains very poorly studied in primates.

Interestingly, there is a communication axis between the liver and the brain, allowing the control and crucial maintenance of the body's metabolic and energy homeostasis [66,67]. Can this communication axis be overactivated or stimulated during viral infections with consequences on the individual's state of health and the fate of the disease? How can a viral infection of the liver in the periphery lead to neurological damage? How can these viruses access the CNS?

Viral infections can cause encephalitis via three main ways. They can use the *hematogenous route* and either cross the BBB by infecting it, crossing it passively or after its permeabilization due to inflammatory response, or use immune cells as a Trojan horse to reach the brain as commonly observed for RVFV [60,68,69]. This route remains quite complicated to address appropriately *ex vivo*. However, analysis of cytokine response to virus infection of *ex vivo* liver culture can already provide information. In this sense, peripheral liver infection can also lead to neuroinflammation indirectly via the *humoral pathway*. Active replication of viruses in hepatocytes, Kupffer cells and/or hepatic endothelial cells, or immune cells (resident and circulating monocytes and macrophages) generates a strong immune and inflammatory response. These immune mediators can disrupt the integrity of the BBB, thereby acting away from the site of infection [70,71]. In fact, the accumulation of cytokines such as Tumor necrosis factor, Interleukin 1 beta-6, and Interleukin 1 beta in the blood in response to infection can cause a deterioration in the integrity of the BBB, allowing the virus to access the CNS. For HCV, infection of the liver triggers a hepatic inflammatory response, damaging the liver through the induction of cell death, activating the immune system, and leading to an acute and high systemic production of pro-inflammatory mediators [72]. This inflammatory response (acute and chronic) can cause a neuroinflammatory response by directly or indirectly crossing the BBB without the virus being present in the CNS and thus contribute to the cognitive degeneration.

A second route that can be evaluated in *ex vivo* models is the production of toxins and metabolites released by the
liver in response to the infection and the impact on the
brain. Indeed, viral infection of the liver inexorably causes
liver damage affecting liver functions, such as detox-
ification, leading to a decrease or even a loss of elimina-
tion or metabolism of toxins and metabolites that are toxic
to the body and cause damage, particularly to the brain. In
the context of hepatic failure occurring during viral he-
patitis (HCV/HBV), a pathology due to a defect in hepatic
detoxification, known as hepatic encephalopathy (HE), is
observed. HE is a term encompassing a broad spectrum of

neuropsychiatric disorders associated with acute and
chronic liver failure resulting from hepatocerebral de-
generation [62,70,71,73,74].

Less documented but possible, *the neural pathway* can be
a gateway for viruses. Indeed, some encephalitic viruses
like WNV [75], ZIKV [76], HSV-1 [77], MeV [78], and
NiV [79] are described for their ability to perform ret-
rograde axonal transport via peripheral nerves. The
vagus nerve represents the main innervation connecting

<figure><img src="image_6.png" /><figcaption>Figure 4</figcaption></figure>

The main *ex vivo* models of the brain and liver used in virology. Illustration of the three *ex vivo* models from the most used to the least in studies on viral infections of the brain and liver. Created in BioRender. MATHIEU, C. (2024) [BioRender.com/x75k870](http://BioRender.com/x75k870).
the liver and brain, raising the question of axonal transport of certain viruses during liver infection. This is an interesting perspective to explore [28,80]. Can these hepatotropic viruses exploit nerve endings to accidentally reach the CNS, thus evading the usual immune response? In this particular case, OLiCs contain all cell populations forming the organ, including peripheral neurons. The permissiveness of neurons in the liver can be assessed during viral tropism evaluation as in other tissues such as organotypic brainstem cultures crossed by the vagus nerve also targeted by several viruses such as SARS-CoV-2 [28].

It is therefore necessary to better understand viral infections at the organ level and the dialog between these two organs during infection. The study of the hepatocerebral axis appears to be promising in understanding viral pathogenesis, with a focus on the early stages of infection that are key to disease development.

## Conclusion

The development and refinement of these *ex vivo* cultures are promising in providing a unique opportunity to study the first events of CNS and liver viral infections (Figure 4). The early stages of infection are a key moment in the understanding of viral pathogenesis, but their investigation is not readily achievable *in vivo*. Despite their relevance, limited work using these brain and liver models has been done on encephalitogenic/hepatotropic viruses. We have reported here how these *ex vivo* models could help in the study of key aspects of encephalitogenic/hepatotropic viruses by gathering the characteristics of various brain and liver cultures and their applications. A significant gap between *ex vivo* brain and liver models was observed; however, this could be bridged by easier accessibility of human liver samples unlike brain. Thus, *ex vivo* models represent a relevant alternative in the modeling of the hepatocerebral axis. In organotypic culture models, the brain and liver are studied alone, but a combination of these two organs at least in a slice context would enable us to mimic the liver-brain communication in an *ex vivo* environment. Based on the starting assumption that the liver will be the first to be infected, we are wondering about the study of elements exclusively produced by the infected liver and their impact on the brain. *Ex vivo* models, particularly organotypic culture models, are relevant for this purpose. Indeed, we would mimic a sequential infection between these two organs to explore the impact of the primary infection of the liver and the elements produced there on the secondary infection of the brain. However, an important part remains to be developed in *ex vivo* models for viral infection to provide relevant contexts that can recapitulate key stages of host-virus interactions in human organ.

## Funding

We thank the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS/Maladies infectieuses émergentes), grant number ECTZ244976 (METINNATE), the Agence Nationale de la Recherche (ANR) ANR-21-CE11-0012 (Heniphase) and (ANR): ANR-24-CE18-6495 (FlavIBLOC).

We acknowledge the Agence Nationale de la Recherche/Agence Innovation Défense/Direction Générale de l'Armement (ViroMetaBlock project; ANR-22-ASTR-0021). This work was carried out with the financial support of the French government through the France 2030 program and the ANRS | MIE, specific project ANRS-23-PEPR-MIE 0008 (NIPAH-LISA).

We thank Intramural CIRI, the project was funded by the Intramural CIRI grant: AO-9-2024/25. We acknowledge that Institut National de la santé et de la Recherche Medicale (INSERM) and Direction Générale de l'Armement (DGA)/Agence Innovation Défense (AID) funded the salary of LC.

## Data Availability

No data were used for the research described in the article.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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The authors describe the method of preparing ex vivo slice culture from the mouse cerebellum and the protocol of studying the effects of West Nile virus infection on cerebellar cells.

28. Ferren M, Favède V, Decimo D, Iampietro M, Lieberman NAP, Weickert J-L, Pelissier R, Mazelier M, Terrier O, Moscona A, Porotto M, Greninger AL, Messaddeq N, Horvat B, Mathieu C: Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection. *Nat Commun* 2021, **12**:5809, https://doi.org/10.1038/s41467-021-26096-z

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This study demonstrates that rat brain organotypic culture support re-
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In this article, the authors demonstrate that human liver organoids are a successful model to study HEV infection and development of antivirals.

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51. Ogire E, Perrin-Cocon L, Figl M, Kundlacz C, Jacquemin C, Hubert S, Aublin-Gex A, Toesca J, Ramière C, Vidalain P-O, Mathieu C, Lotteau V, Diaz O: **Dengue virus dependence on glucokinase activity and glycolysis Confers Sensitivity to NAD(H) biosynthesis inhibitors.** *Antivir Res* 2024, **228**:105939, https://doi.org/10.1016/j.antiviral.2024.105939.

The authors describe for the first time the development of an OLiCs (hamster) on an air-liquid interface for studying DENV infection. This new ex vivo model was used to study viral replication of dengue virus and a therapeutic candidate against DENV infection.

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56. Tsai T-T, Chen C-L, Lin Y-S, Chang C-P, Tsai C-C, Cheng Y-L, Huang C-C, Ho C-J, Lee Y-C, Lin L-T, Jhan M-K, Lin C-F: **Microglia retard dengue virus-induced acute viral encephalitis.** *Sci Rep* 2016, **6**:27670, https://doi.org/10.1038/srep27670

57. Amorim JFS, Azevedo AS, Costa SM, Trindade GF, Basílio-de-Oliveira CA, Gonçalves AJS, Salomão NG, Rabelo K, Amaral R,
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58. Le Hir A, Durand GA, Boucraut J, Garnier A, Mura M, Diamantis S, Carles M, Durand C, Schweitzer C, Audouard C, Decroix V, Boyez R, Van Dendriessche A, Leclancher A, Kaphan E, Barbat du Closel L, Verdon R, du Cheyron D, Vabret A, Vergnon D, Grard G, Charrel R, de Lamballerie X, Eldin C: **Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for Arboviruses with clinical and immunological insights.** *J Travel Med* 2024, **31**:taad160, https://doi.org/10.1093/jtm/taad160

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60. Dodd KA, McElroy AK, Jones TL, Zaki SR, Nichol ST, Spiropoulou CF: **Rift valley fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model.** *PLoS Negl Trop Dis* 2014, **8**:e2874, https://doi.org/10.1371/journal.pntd.0002874

61. Quellec J, Pédarrieu A, Piro-Mégy C, Barthelemy J, Simonin Y, Salinas S, Cêtre-Sossah C: **Rift Valley fever virus modulates apoptosis and immune response during infection of human astrocytes.** *Emerg Microbes Infect* 2023, **12**:2207672, https://doi.org/10.1080/22221751.2023.2207672

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This *in vivo* study demonstrates that restricting RVFV liver replication reduces acute hepatitis development and instead leads to late-onset encephalitis in C57BL/6 mice.

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68. Wilson LR, McElroy AK: **Rift Valley fever virus encephalitis: viral and host determinants of pathogenesis.** *Annu Rev Virol* 2024, **11**:309-325, https://doi.org/10.1146/annurev-virology-093022-011544

69. Quellec J, Piro-Megy C, Cannac M, Nisole S, Marty FH, Gosselet F, Shimizu F, Kanda T, Cêtre-Sossah C, Salinas S: **Rift Valley fever virus is able to cross the human blood-brain barrier in vitro by direct infection with no deleterious effects.** *J Virol* 2024, **98**:e0126724, https://doi.org/10.1128/jvi.01267-24.
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70. Ružić M, Rajić N, Nikolašević Ž, Spasić A, Pete M, Ignjatović VB: **Is there a connection between neurocognitive profile in treatment naïve non-cirrhotic HCV patients and level of systemic inflammation?** *J Neurovirol* 2023, **29**:723-730, https://doi.org/10.1007/s13365-023-01184-6

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73. Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G, Merli M, Montagnese S, Romero-Gomez M, Schnitzler A, Taylor-Robinson SD, Vilstrup H: **Hepatic encephalopathy.** *Nat Rev Dis Prim* 2022, **8**:43, https://doi.org/10.1038/s41572-022-00366-6

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77. DuRaine G, Johnson DC: **Anterograde transport of α-herpesviruses in neuronal axons.** *Virology* 2021, **559**:65-73, https://doi.org/10.1016/j.virol.2021.02.011

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79. Munster VJ, Prescott JB, Bushmaker T, Long D, Rosenke R, Thomas T, Scott D, Fischer ER, Feldmann H, de Wit E: **Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route.** *Sci Rep* 2012, **2**:736, https://doi.org/10.1038/srep00736

80. Constant O, Maarifi G, Blanchet FP, Van de Perre P, Simonin Y, Salinas S: **Role of dendritic cells in viral brain infections.** *Front Immunol* 2022, **13**:862053, https://doi.org/10.3389/fimmu.2022.862053.

This review highlights an important contribution of DCs in the development and the consequences of viral brain infections.