bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic infection ruined NK cell-mediated help on influenza virus-specific CTLs
Authors: Zheng Jian , Liu Yuan , Liu Yinping , Huang Lei , Xiang Zheng , Lam Kwok-Tai , Lv Aizhen , Mao Huawei , Lau Yu-Lung , Tu Wenwei 
Published: January 2023

Abstract
Host resistance against influenza A virus infection relies on the efficient collaboration of innate and adaptive immune response. Being a major component of innate immune system, NK cells have been confirmed to limit the replication and spread of influenza virus during early infection. However, their roles in the generation of virus-specific CTLs response still remain exclusive. Consistent with our in vitro study on human NK cells, here we firstly confirmed that murine NK cells could be directly infected with mouse-adaptive influenza A PR8 virus in vivo under both systemic and local infection. However, only systemic infection resulted in severe reduction and dysfunction of spleen NK cells, which was accompanied with the poor antigen-specific killing and IFN-γ secretion rather than the decrease in quantity of CTLs during the acute phase of infection. Importantly, the adoptive transfer of spleen NK cells from mice suffering from local infection rescued the impaired CTLs in systemic influenza virus-infected mice, whereas no similar effects could be observed by using NK cells from healthy mice. Taken together, our results demonstrated that NK cell-mediated help on the generation of functional influenza virus-specific CTLs was infection-dependent and determined by the dose of infection. This study provided some important information for developing novel NK-cell-targeted strategy against severe influenza infection.
CX3CR1 regulates type 2 immune response in respiratory syncytial virus infected newborn mice
Authors: Das Sudipta , Raundhal Mahesh Ramdas , Chemmannur Sijo Varghese , Huff Rachael , Morse Christina , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis and pneumonia in infants requiring hospitalization. In mouse models of RSV infection, multiple studies have highlighted the ability of RSV to induce a type 2 immune response with associated mucus production and airway inflammation. Structurally RSV has two surface glycoproteins, F and G in the viral envelope. Previous studies have shown that the G-protein helps the virus to attach to the host cell by binding to the chemokine receptor CX3CR1 due to the presence of a CX3C motif and this interaction appears to be linked in the pathogenesis of RSV disease. However, the pathways that regulate RSV-induced immune response and pulmonary pathology are not well understood. Therefore, to study the functional relevance of CX3CR1 in the context of viral clearance and host pathology, we used CX3CR1gfp/gfp knock-in mice in which the homozygous mutant mice lack a functional CX3CR1 receptor. 5 day old newborn mice were infected with RSV intranasally and the lungs were harvested to isolate RNA and protein 4 day post infection. We observed that unlike WT mice, CX3CR1gfp/gfp mutant mice fails to induce the expression of type 2 cytokines IL-5 and IL-13 upon RSV infection. Additionally, two key genes Muc5ac and Gob5, involved in cell hyperplasia, mucus production and airway inflammation were found to be induced upon RSV infection in WT while those were suppressed in mutant mice. These observations suggest a regulatory function of CX3CR1 in the establishment of RSV-mediated type 2 immune response in the host. Our ongoing studies are focused on elucidating the mechanism by which CX3CR1 signaling regulates type 2 immune response and associated pathology in the RSV-infected host.
Early onset and persistence of metabolic alterations in exhausted T cells is regulated by PD-1
Authors: Bengsch Bertram R , Johnson Andy L , Kurachi Makoto , Odorizzi Pamela , Pauken Kristen E , Attanasio John , Wherry E. John 
Published: January 2023

Abstract
Dynamic reprogramming of metabolism is essential for T cell effector function and formation of memory. However, regulation of cellular metabolism in exhausted T cells in chronic infections and cancer is poorly understood. Here we found that as early as the first week of chronic LCMV infection, before severe T cell dysfunction becomes established, virus-specific CD8 T cells are already unable to match the bioenergetic demands of effector CD8 T cells generated during acutely resolving LCMV infection. Suppression of T cells bioenergetics involves restriction of glucose uptake and utilization, despite the up-regulation of multiple other metabolic pathways. The inhibitory receptor PD-1 controlled the development of this early glycolytic defect as well as mitochondrial mass and quality in the presence of persisting mTOR signaling. The suppression of glycolysis and mitochondrial metabolism in exhausted T cells persists into established chronic infection. Therapeutic reinvigoration of exhausted T cells by PD-L1 blockade reprogrammed the metabolism of PD-1Int but not the terminal PD-1Hi subset of exhausted T cells. These data highlight a key metabolic control event early in T cell exhaustion that precedes major transcriptional changes. Our findings also suggest that manipulating metabolism in combination with checkpoint blockade may enhance therapeutic outcomes.
Identification of a locus on chromosome 1 regulating IL-17-producing γδ T cells and mortality after influenza infection.
Authors: Dienz Oliver , DeVault Victoria L , Wallace Aaron M , Suratt Benjamin T. , Boyson Jonathan E 
Published: January 2023

Abstract
γδ T cells are an evolutionary conserved T cell subset with innate-like effector functions. We had previously identified a locus on chromosome 1 encompassing the Slam gene family that regulates the innate-like T cell compartment. To characterize this region further, we generated a B6.129 congenic mouse strain in which a 1.1 Mbp region (chr. 1: 171.05–172.12) from the 129X1/SvJ strain was introgressed onto the C57BL/6J background, and evaluated its effect on the host immune response in influenza-infected mice. Upon infection, we observed a significant and sustained increase in the number of lung γδ T cells in B6.129c2 congenic mice. A comparison of γδ T cell function revealed that a significantly greater fraction of B6.129c2 γδ T cells were producing IL-17A versus their B6 counterparts. These differences were subset-specific as they were observed in Vγ4 and at least one other Vγ subset, but not in Vγ1 T cells. Those IL-17-producing Vγ subsets accounted for most of the increase in B6.129c2 lung γδ T cell numbers and they displayed an attenuated cell surface expression profile of Slam family receptors. Finally, since enhanced IL-17 responses have been associated with immunopathology after influenza infection, we assessed the effect of the congenic interval on survival. We found that the survival of B6.129c2 congenic mice is significantly lower compared with B6 mice after influenza infection. Taken together, our data suggest that natural genetic variations at this locus significantly impact both IL-17A production by lung γδ T cells and mortality after influenza infection.
Modulation of cellular immune response by 2′-5′ Oligoadenylate Synthetase - like (OASL) proteins during DNA virus infection
Authors: Ghosh Arundhati , Sampath Padmavathi , Zhu Jianzhong , Hornung Veit , Thorne Stephen , Sarkar Saumendra N 
Published: January 2023

Abstract
Oligoadenylate Synthetase-like (OASL) is a type I interferon (IFN) stimulated gene, strongly induced following virus infection, but lacks enzymatic activity to synthesize 2′–5′ oligoadenylates. We show that human OASL, and its functional ortholog mouse Oasl2 are critical modulators of cellular antiviral signaling. During RNA virus infection, OASL binds the RNA-sensor, RIG-I, and enhances RIG-I signaling by mimicking one of the RIG-I-ligands, K63-linked polyubiquitin [p(Ub)], thus exerting an antiviral activity. In contrast, by binding the DNA-sensor, cyclic GMP-AMP synthase (cGAS), OASL negatively regulates IFN induction and restricts inflammation in the context of DNA virus infections, some of which can establish persistent infection.
Human OASL or mouse Oasl2 knockout cells showed enhanced IFN induction when stimulated either with intracellular DNA or DNA viruses such as Vaccinia and Herpes simplex virus. Consequently, Oasl2 knockout mice showed delayed and reduced Vaccinia virus spread and mortality. Additionally, OASL or Oasl2 affected IFN induction when stimulated with intracellular DNA, but not with cGAMP, indicating the upstream effect of OASL is on cGAS stimulation and not on STING stimulation. Mechanistically, OASL specifically interacted with cGAS, and inhibited its activity. Together these results establish the unique ability of OASL to differentially modulate RNA and DNA virus replication and IFN induction.
NLRP3 plays a major role in inflammasome activation during Mycoplasma pneumoniae infection
Authors: Segovia Jesus A , Chang Te-Hung , Pandranki Lavanya , Kannan Thirumalai R , Baseman Joel B 
Published: January 2023

Abstract
Mycoplasma pneumoniae (Mp) is a common bacterial pathogen that causes acute and chronic airway diseases in humans and is a leading cause of bacterial community-acquired pneumonia and is implicated in initiation and exacerbation of asthma. Mp infection triggers a strong inflammatory response driven by interleukin-1β (IL-1β). Mp produces the Community-Acquired Respiratory Distress Syndrome (CARDS) toxin, which is highly expressed during infection and specifically activates the nod-like receptor family protein 3 (NLRP3) inflammasome. However, the significance of the NLRP3 inflammasome during Mp infection is unclear. The goal of our study is to characterize the inflammasome-mediated response during Mp infection.
Wild-type (WT) and NLRP3 knockout (KO) bone-marrow derived macrophages (BMDMs) were infected with Mp and levels of proinflammatory cytokines and chemokines were measured by ELISA and immunoblot. Additionally, WT and NLRP3 KO C57 mice were inoculated intranasally with Mp and analyses were performed on cytokines and lung histopathology.
Following Mp infection, NLRP3 KO BMDMs secreted significantly less IL-1β compared to WT BMDMs, yet IL-6 levels were similar. Analyses of bronchoalveolar lavage and lung tissue from Mp-infected WT and NLRP3 KO mice revealed a unique proinflammatory cytokine response, considerably enhanced disease and impaired bacterial clearance in NLRP3 KO mice.
Our studies identified NLRP3 as a critical regulator of proinflammatory cytokine response and pathology during Mp infection. Future studies will focus on characterizing immune cell trafficking in the lungs during Mp infection and determining if Mp-related inflammasome activity is an ontogenic factor in initiating and exacerbating asthma.
Opposing roles of AIM2 inflammasome and type I interferon signaling in Francisella infection
Authors: Zhu Qifan , Man Si Ming , Karki Rajendra , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Inflammasomes are crucial for mediating protection against microbial infection. Type I interferon (IFN) signaling is required for driving activation of the AIM2 inflammasome in macrophages in response to infection by Francisella tularensis subspecies novicida (F. novicida). Here, we showed that compared with infected wild-type mice, mice lacking the type I IFN receptor IFNAR2 exhibited increased resistance towards F. novicida infection, whereas mice lacking AIM2 were more susceptible. In addition, mice lacking IRF9, a core component of IFN-stimulated gene factor 3 that transduces type I IFN signaling, showed increased resistance following infection. These results suggested that while type I IFN signaling and AIM2 were essential for activation of the Francisella-induced inflammasome in macrophages, these components have strikingly contrasting effects in vivo. Importantly, we found that mice lacking both AIM2 and IFNAR2 were more resistant than infected wild-type mice and mice lacking AIM2. Taken together, we identified type I IFN signaling as a dominant regulator of anti-microbial activity during F. novicida infection in vivo even in the absence of AIM2 responses.
A protective role of hepcidin in bacterial pneumonia
Authors: Chen QiXing , Yang Yang , Song Shengwen , Fang XiangMing , Shu Qiang 
Published: January 2023

Abstract

Objective
Hepcidin is a b-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infectious disease such as bacterial pneumonia.

Methods
Pneumonia was induced by intratracheally administration of Gram-negative bacterium Escherichia coli or Pseudomonas aeruginosa, or Gram-positive bacterium Staphylococcus aureus. Hepcidin level in lung tissue was measured by means of immunohistological staining. Hepcidin-overexpressing adenovirus and control adenovirus were intratracheally injected into mice. The survival rates of hepcidin genetically engineered mice suffered from pneumonia were monitored for 72 hours.

Results
Hepcidin was mainly expressed on airway epithelial cells in mouse lung tissue. The hepcidin levels were gradually decreased after pneumonia onset, and recovered at 48 hours after Escherichia coli and Staphylococcus aureus infection, and at 72 hours after Pseudomonas aeruginosa infection. Hepcidin knock-out mice were more susceptible to Escherichia coli pneumonia and only 37.5% of them were survived for 72 hours (80.0% for wild-type mice; P&lt;0.05). In contrast, intratracheal overexpression of hepcidin protected mice from lethal Escherichia coli infection (survival rate: 100.0% for hepcidin overexpressing mice, and 41.7% for control mice; P&lt;0.01).

Conclusions
Hepcidin plays an important role in protection against bacterial pneumonia, and the mechanism needs further investigation.
Mannose-binding lectin (MBL) is the main complement activator on Aspergillus fumigatus conidia under immunocompromised conditions
Authors: Rosbjerg Anne , Genster Ninette , Hansen Katrine Pilely , Skjoedt Mikkel-Ole , Gal Peter , Stahl Gregory L , Garred Peter 
Published: January 2023

Abstract
Aspergillus fumigatus is normally a non-pathogenic fungus, but in immunocompromised patients this fungus becomes highly pathogenic. Complement activation are thought to be of crucial importance for elimination of A. fumigatus. However, which of the three complement pathways that are important under immunocompromised conditions are only partly understood.
Conidia from a clinical isolate of A. fumigatus were co-incubated with serum before complement activation products C4b, C3b and TCC were measured in flow cytometry. Besides normal (NHS) and complement deficient sera plus complement inhibitors, we used umbilical cord serum (UCS) to mimic a compromised immune defense reflected in the low immunoglobulin (Ig) levels.
In NHS, the classical pathway was the dominant initiator with the alternative pathway providing a strong C3b amplification. Classical pathway is known to be initiated via C1q binding to Ig, whereas MBL and ficolin-2 from the lectin pathway bind the fungus directly. UCS conveyed low IgG and no IgM binding to the conidia, and we observed that complement activation on A. fumigatus in UCS was predominantly MBL dependent. UCS with low MBL had significantly lower C3b deposition than serum from NHS with low MBL. Moreover, a close positive correlation between MBL levels and C3b deposition in UCS (Spearman r = 0.79, p &lt; 0.0001, n = 23) was observed. The significance of MBL was emphasized by decreased neutrophilic phagocytosis of conidia via MBL inhibition in C1q−/− serum.
We conclude that MBL is the main complement activator and phagocytosis initiator of A. fumigatus conidia in individuals with low Ig levels. This suggests a crucial role for the lectin pathway in protection against infection of A. fumigatus in immunocompromised patients.
Identification of an amphipathic helix within IFITM3 that promotes inhibition of influenza virus
Authors: Chesarino Nicholas M , McMichael Temet M , Zhang Lizhi , Davis Matthew J , Soewarna Victoria , Doering Rachel F , Yount Jacob S 
Published: January 2023

Abstract
Interferon-induced transmembrane protein 3 (IFITM3) inhibits influenza virus fusion with endosomes by altering cellular membrane properties through mechanisms that are largely uncharacterized. In order to identify regions of secondary structure within IFITM3 that may contribute to its mechanism of action, we performed structural predictions using the I-TASSER and PSSpred algorithms. Insterestingly, we identified a 10-amino acid region of likely helicity that possesses an amphipathic distribution of amino acids. Consistent with the known role of amphipathic helices in altering membrane properties, we observed that cells expressing a helix-deleted mutant of IFITM3 were infected with influenza virus at a 4-fold higher rate than cells expressing WT IFITM3. Confirming that the amphipathicity of this helix contributes to antiviral activity, single, double and triple alanine mutations of the three residues making up the hydrophilic face of the helix progressively decreased antiviral activity of IFITM3, as did single polar mutations in the hydrophobic face of the helix, or single amino acid insertions that disrupted amphipathicity. Amino acid sequence alignments suggest that amphipathicity in this region is highly conserved in IFITMs throughout evolution. Overall, we utilized bioinformatics methods coupled with functional infectivity assays to provide the first evidence that IFITM3 utilizes an amphipathicity-based mechanism for inhibition of viruses.
Reciprocal regulation of Th17 and Treg differentiation by PKC-θ-phosphorylated steroid receptor co-activator1
Authors: Sen Subha , Sun Zuoming 
Published: January 2023

Abstract
Interleukin 17 (IL-17) producing T helper cells (Th17) differentiation is regulated partially by TCR stimulated PKC-θ activation. In this report, we show that steroid receptor co-activator1 (SRC1), a key RORγT transcriptional co-activator is phosphorylated by PKC-θ and acts as a critical modulator to induce Th17 development while potentially inhibiting iTreg development. SRC1 phosphorylated by PKC-θ is required for optimal interaction between SRC1 and RORγT, the lineage defining transcription factor, to stably bind to the consensus DNA sites and induce productive transcriptional outcome. Moreover, SRC1 recruits CARM1, a protein arginine methyltransferase, to enhance the RORγT target site histone arginine methylation, thereby maintaining the target site availability for RORγT and hence contributing additionally to further stimulate the magnitude of IL-17 production. Herein we also reveal for the first time, that phosphor-SRC1 can reverse the inhibitory interaction between Foxp3 and RORγT leading to the displacement of inhibitory Foxp3 and thereby reversing the suppressive antagonizing effect of Foxp3 on RORγT, favoring Treg to Th17 balance shift. In mice, lack of SRC1 resulted in diminished Th17 development but enhanced Treg differentiation, resulting in better protection from autoimmune encephalomyelitis. Thus, PKC-θ modified SRC1 is identified as a major signaling checkpoint which determines the Th17-iTreg differentiation fate diverging from a common developmental pathway.
M. smegmatis vaccination reveals the mycobacterial ribosome as a potential CD4+ Tcell enhancing vaccine target
Authors: Kennedy Steven C , Johnson Alison J , Sette Alessandro , Chan John , Jacobs William R , Porcelli Steven A 
Published: January 2023

Abstract
Mycobacterium tuberculosis(Mtb) is an airborne pathogen that infects one third of the world’s population. To date no vaccine has had major success in reducing the enormous global burden of disease from this infection. Critical to the control of Mtb is the ability of a vaccine to induce a strong CD4+ Tcell response. The currently available vaccine, M. bovis BCG, is of limited efficacy, potentially due to its retention of immune evasion mechanisms that actively inhibit the host presentation of critical antigens to CD4+ Tcells. Examining antigens that are hidden during a BCG immunization may lead to identification of novel vaccine targets. Our lab has previously identified an M. smegmatis based vaccine, IKEPLUS, which elicits a strong CD4+ Tcell response leading to significantly enhanced protection to Mtb over BCG vaccination. M. smegmatis is a non-pathogenic mycobacterium that has not retained the ability to disrupt antigen presentation to the host immune system. Examination of the CD4+ Tcell response to IKEPLUS and BCG has identified the mycobacterial ribosome as a major immunogenic target in the M. smegmatis based IKEPLUS, but not in BCG. This dichotomy in the immune response led us to further characterize the ribosome and evaluate its protein constituents as potential vaccine targets. The ribosome is composed of 57 individual proteins; of these 57 proteins, we have identified 20 as immunogenic, and identified minimal CD4+ Tcell epitopes for 10 of the 20 identified proteins. These findings have led us to begin development of a mycobacterial ribosome based vaccine to enhance the currently existing BCG regimen. This approach will allow us to complement what we believe is a critical flaw of BCG while retaining the widely used BCG vaccination regimen.
IgG1 and Th1 responses to DosR, Rpf and active growth phase antigens of Mycobacterium tuberculosis in Brazilian tuberculosis patients.
Authors: Teixeira Henrique Couto , Mattos Ana Márcia Menezes , Almeida Caroline Souza , Abad Lily Paola Martinez , Franken Kees , Ottenhoff Tom H. M. 
Published: January 2023

Abstract
Tuberculosis (TB) is serious problem worldwide. New antigens from Mycobacterium tuberculosis are being investigated in order to improve the diagnosis of latent TB infection and TB disease. In this study, serum levels of IgG1 antibodies against active growth phase antigens (ESAT-6/CFP-10, Rv0717 and Rv3353), dormancy-related (DosR) antigens (Rv1733, Rv1737, Rv2029 and Rv2628), and resuscitation promoting factors (Rpfs Rv0867 and Rv2389) were evaluated in patients with TB before and after chemotherapy using ELISA. Antigen-induced IFN-γ, TNF-α, IL-17, IL-10 and IL-4 were evaluated in supernatants of PBMC cultures. Our results indicate that patients with pulmonary TB express high levels of IgG1 antibodies against ESAT-6/CFP-10, Rv0717, Rv3353, Rv1733, Rv2029 and Rv2628 Rv0867 in the active phase of the disease in comparison to healthy controls (p&lt;0.001). These levels declined to control levels after the completion of six months treatment. ROC analysis confirmed the good performance of Rv0717, Rv1733, Rv3353, Rv0867, Rv2029 and Rv2628 antigens. Interestingly, Rv0717 and Rv1733 antigens induced an IgG1 peak response after 1–3 months of chemotherapy (P&lt;0.01). Similarly, IFN-γ and TNF-α peaked early during treatment in response to ESAT-6/CFP-10, Rv1733 and Rv2029, and declined to control levels after 6 months of chemotherapy. The study groups did not differ in respect to IL-17, IL-10 and IL-4. Taken together, these data further reinforce a possible correlation of IgG1 production with Th1 responses in TB. Moreover, detecting IgG1 antibodies against M. tuberculosis antigens, including DosR and Rpf proteins, may represent an additional tool in the diagnosis of tuberculosis.
Financial support: FAPEMIG, CNPq and CAPES, EU and NWO-TOP.