Innate Immune Responses against Viral Infection and Its Suppression by Viral Proteins

Influenza A viruses (IAV) can infect a broad range of animal hosts, including humans. In humans, IAV causes seasonal annual epidemics and occasional pandemics, representing a serious public health and economic problem, which is most effectively prevented through vaccination. The defense mechanisms that the host innate immune system provides restrict IAV replication and infection. Consequently, to successfully replicate in interferon (IFN)-competent systems, IAV has to counteract host antiviral activities, mainly the production of IFN and the activities of IFN-induced host proteins that inhibit virus replication. The IAV multifunctional proteins PA-X and NS1 are virulence factors that modulate the innate immune response and virus pathogenicity. Notably, these two viral proteins have synergistic effects in the inhibition of host protein synthesis in infected cells, although using different mechanisms of action. Moreover, the control of innate immune responses by the IAV NS1 and PA-X proteins is subject to a balance that can determine virus pathogenesis and fitness, and recent evidence shows co-evolution of these proteins in seasonal viruses, indicating that they should be monitored for enhanced virulence. Importantly, inhibition of host gene expression by the influenza NS1 and/or PA-X proteins could be explored to develop improved live-attenuated influenza vaccines (LAIV) by modulating the ability of the virus to counteract antiviral host responses. Likewise, both viral proteins represent a reasonable target for the development of new antivirals for the control of IAV infections. In this review, we summarize the role of IAV NS1 and PA-X in controlling the antiviral response during viral infection.

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Organotypic modeling of SARS-CoV-2 lung and brainstem infection

10.21203/rs.3.rs-122126/v1 ◽

2020 ◽

Author(s):

Marion Ferren ◽

Valérie Favede ◽

Didier Decimo ◽

Mathieu Iampietro ◽

Nicole A. P. Lieberman ◽

...

Keyword(s):

Central Nervous System ◽

Immune Responses ◽

Viral Infection ◽

Central Nervous System Infection ◽

Tissue Level ◽

Innate Immune ◽

Innate Immune Responses ◽

Organotypic Cultures ◽

Neurological Sequelae ◽

Global Pandemic

Abstract SARS-CoV-2 has caused a global pandemic of Covid-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also lead to central nervous system infection and neurological sequelae. We developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer the unique opportunity to study the early steps of the pathogenesis and screening of antivirals. Using these models, we validated the early tropism of the virus in the lung and demonstrated that SARS-CoV2 can infect brainstem and cerebellum, mainly by targeting granular neurons. Viral infection induced specific interferon and innate immune responses with patterns specific to each organ along with apoptotic, necroptotic, and pyroptotic cell death. Overall, our data illustrate the potential of rapidly modeling complex tissue level interactions of viral infection in a newly emerged virus.

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Faculty Opinions recommendation of CD8 T cells in innate immune responses: using STAT4-dependent but antigen-independent pathways to gamma interferon during viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.723553947.793501609 ◽

2014 ◽

Author(s):

Tian Wang

Keyword(s):

T Cells ◽

Immune Responses ◽

Viral Infection ◽

Cd8 T Cells ◽

Gamma Interferon ◽

Innate Immune ◽

Innate Immune Responses

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Host–Viral Interactions in the Pathogenesis of Ulcerative Colitis

International Journal of Molecular Sciences ◽

10.3390/ijms221910851 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10851

Author(s):

Torunn Bruland ◽

Ann Elisabet Østvik ◽

Arne Kristian Sandvik ◽

Marianne Doré Hansen

Keyword(s):

Ulcerative Colitis ◽

Immune Responses ◽

Viral Infection ◽

Protective Immunity ◽

Innate Immune ◽

The Other ◽

Mucosal Inflammation ◽

Innate Immune Responses ◽

Rapid Release ◽

Viral Interactions

Ulcerative colitis is characterized by relapsing and remitting colonic mucosal inflammation. During the early stages of viral infection, innate immune defenses are activated, leading to the rapid release of cytokines and the subsequent initiation of downstream responses including inflammation. Previously, intestinal viruses were thought to be either detrimental or neutral to the host. However, persisting viruses may have a role as resident commensals and confer protective immunity during inflammation. On the other hand, the dysregulation of gut mucosal immune responses to viruses can trigger excessive, pathogenic inflammation. The purpose of this review is to discuss virus-induced innate immune responses that are at play in ulcerative colitis.

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Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection

Nature Communications ◽

10.1038/s41467-021-26096-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marion Ferren ◽

Valérie Favède ◽

Didier Decimo ◽

Mathieu Iampietro ◽

Nicole A. P. Lieberman ◽

...

Keyword(s):

Immune Responses ◽

Viral Infection ◽

Tissue Level ◽

Innate Immune ◽

Innate Immune Responses ◽

Organotypic Cultures ◽

Neurological Sequelae ◽

Global Pandemic ◽

Rapid Modeling ◽

The Brain

AbstractSARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.

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Released Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral Infection

Journal of Virology ◽

10.1128/jvi.01291-18 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 9

Author(s):

Hyun-Cheol Lee ◽

Eun-Seo Lee ◽

Md Bashir Uddin ◽

Tae-Hwan Kim ◽

Jae-Hoon Kim ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Viral Infection ◽

Innate Immune Response ◽

Trna Synthetase ◽

Innate Immune ◽

Full Length ◽

Type I ◽

Innate Immune Responses

ABSTRACT Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during bacterial infection and primes the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of viral infection and functions as an antiviral cytokine. Treatment of cells with recombinant WRS protein promotes the production of inflammatory cytokines and type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4−/− or MD2−/− bone marrow-derived macrophages (BMDMs). Intravenous and intranasal administration of recombinant WRS protein induces an innate immune response and blocks viral replication in vivo. These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to viral infection as well as to bacterial infection. IMPORTANCE ARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo. Thus, we consider WRS to be a member of the antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.

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Hepatitis B Virus–Hepatocyte Interactions and Innate Immune Responses: Experimental Models and Molecular Mechanisms

Seminars in Liver Disease ◽

10.1055/s-0039-1685518 ◽

2019 ◽

Vol 39 (03) ◽

pp. 301-314 ◽

Cited By ~ 1

Author(s):

Emmanuel Thomas ◽

Thomas F. Baumert

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Immune Responses ◽

Viral Infection ◽

Signaling Pathways ◽

Viral Pathogenesis ◽

Innate Immune ◽

Innate Immune Responses ◽

Host Interactions ◽

B Virus

AbstractChronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide. While current therapeutic approaches can efficiently control viral infection, efficient curative antivirals are absent. The understanding of virus–hepatocyte interactions and sensing of viral infection is an important prerequisite for the development of novel antiviral therapies for cure. Hepatocyte intrinsic innate immunity provides a rapid first line of defense to combat viral infection through the upregulation of antiviral and inflammatory genes. However, the functional relevance of many of these antiviral signaling pathways in the liver and their role in HBV pathogenesis is still only partially understood. The recent identification of intracellular RNA and DNA sensing pathways and their involvement in disease biology, including viral pathogenesis and carcinogenesis, is currently transforming our understanding of virus–host interactions. Here the authors review the current knowledge on intrinsic antiviral innate immune responses including the role of viral nucleic acid sensing pathways in the liver. Since HBV has been designated as a “stealth virus,” the study of the impact of HBV on signaling pathways in the hepatocyte is of significant interest to understand viral pathogenesis. Characterizing the mechanism underlying these HBV–host interactions and targeting related pathways to enhance antiviral innate responses may open new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with chronic HBV infection.

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Human cytomegalovirus UL48 deubiquitinase primarily targets innermost tegument proteins pp150 and itself to regulate their stability and protects virions from inclusion of ubiquitin conjugates

Journal of Virology ◽

10.1128/jvi.00991-21 ◽

2021 ◽

Author(s):

Ki Mun Kwon ◽

Young Eui Kim ◽

Myoung Kyu Lee ◽

Woo-Chang Chung ◽

Seokhwan Hyeon ◽

...

Keyword(s):

Immune Responses ◽

Active Site ◽

Viral Proteins ◽

Innate Immune ◽

Wild Type Virus ◽

Innate Immune Responses ◽

Wild Type ◽

Tegument Proteins ◽

The Stability

Viral deubiquitinases (DUBs) regulate cellular innate immunity to benefit viral replication. In human cytomegalovirus (HCMV), the UL48-encoded DUB regulates innate immune responses including NF-κB signaling. Although UL48 DUB is known to regulate its stability via auto-deubiquitination, its impact on other viral proteins is not well understood. In this study, we investigated the role of UL48 DUB in regulating the ubiquitination of viral proteins by comparing the levels of ubiquitinated viral peptides in wild-type and DUB active-site mutant virus-infected cells using mass spectrometry. We found that ubiquitinated peptides were increased in DUB-mutant virus infection for 90% of viral proteins with the innermost tegument proteins pp150 (encoded by UL32) and pUL48 itself being most significantly affected. The highly deubiquitinated lysine residues of pUL48 were mapped within its N-terminal DUB domain and the nuclear localization signal. Among them, the arginine substitution of lysine 2 (K2R) increased pUL48 stability and enhanced viral growth at low multiplicity of infection, indicating that K2 auto-deubiquitination has a role in regulating pUL48 stability. pUL48 also interacted with pp150 and increased pp150 expression by downregulating its ubiquitination. Furthermore, we found that, unlike the wild-type virus, mutant viruses expressing the UL48 protein with the DUB-domain deleted or DUB active-site mutated contain higher levels of ubiquitin conjugates, including the ubiquitinated forms of pp150, in their virions. Collectively, our results demonstrate that UL48 DUB mainly acts on the innermost tegument proteins pp150 and pUL48 itself during HCMV infection and may play a role in protecting virions from the inclusion of ubiquitin conjugates. Importance Herpesviruses encode highly conserved tegument proteins that contain deubiquitinase (DUB) activity. Although the role of viral DUBs in the regulation of host innate immune responses has been established, their roles in the stability or function of viral proteins are not well understood. In this study, we performed a comparative analysis of the levels of ubiquitinated viral peptides between wild-type and DUB-inactive HCMV infections and demonstrate that the innermost tegument proteins pp150 and pUL48 (DUB itself) are major targets of viral DUB. We also show that ubiquitinated viral proteins are effectively incorporated into the virions of DUB mutant viruses but not the wild-type virus. Our study demonstrates that viral DUBs may play important roles in promoting the stability of viral proteins and inhibiting the inclusion of ubiquitin conjugates into virions.

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Viral Induction of Central Nervous System Innate Immune Responses

Journal of Virology ◽

10.1128/jvi.79.7.4369-4381.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4369-4381 ◽

Cited By ~ 34

Author(s):

J. D. Rempel ◽

L. A. Quina ◽

P. K. Blakely-Gonzales ◽

M. J. Buchmeier ◽

D. L. Gruol

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Responses ◽

Viral Infection ◽

Hepatitis Virus ◽

Gene Array ◽

Innate Immune ◽

Cns Infection ◽

Innate Immune Responses ◽

Infected Cells

ABSTRACT The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA isolated from virally and sham-infected cultures, were compared with parallel protein assays for cytokine, chemokine, and cell surface markers. Of the 126 transcripts found to be differentially expressed between viral and sham infections, the majority were related to immunological responses. Virally induced increases in interleukin-6 and tumor necrosis factor alpha mRNA and protein expression correlated with the genomic induction of acute-phase proteins. Genomic and protein analysis indicated that viral infection resulted in prominent expression of neutrophil and macrophage chemotactic proteins. In addition, mRNA expression of nonclassical class I molecules H2-T10, -T17, -M2, and -Q10, were enhanced three- to fivefold in virus-infected cells compared to sham-infected cells. Thus, upon infection, resident brain cells induced a breadth of innate immune responses that could be vital in directing the outcome of the infection and, in vivo, would provide signals which would summon the peripheral immune system to respond to the infection. Further understanding of how these innate responses participate in immune protection or immunopathology in the CNS will be critical in efforts to intervene in severe encephalitis.

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Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip

10.1101/2021.04.26.441498 ◽

2021 ◽

Author(s):

Haiqing Bai ◽

Longlong Si ◽

Amanda Jiang ◽

Chaitra Belgur ◽

Roberto Plebani ◽

...

Keyword(s):

Endothelial Cells ◽

Immune Responses ◽

Viral Infection ◽

Human Lung ◽

Innate Immune ◽

H3n2 Virus ◽

Type I ◽

Innate Immune Responses ◽

Lung Alveolus

ABSTRACTMechanical forces associated with breathing play a fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with the influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress the production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.

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