Posttranscriptional Control of Type I Interferon Genes by KSRP in the Innate Immune Response against Viral Infection

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

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Cryptosporidium parvumInfection Rapidly Induces a Protective Innate Immune Response Involving Type I Interferon

The Journal of Infectious Diseases ◽

10.1086/644601 ◽

2009 ◽

Vol 200 (10) ◽

pp. 1548-1555 ◽

Cited By ~ 31

Author(s):

Farah M. Barakat ◽

Vincent McDonald ◽

Graham R. Foster ◽

Michael G. Tovey ◽

Daniel S. Korbel

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Type I Interferon ◽

Innate Immune ◽

Type I

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The brain parenchyma has a type I interferon response that can limit virus spread

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618157114 ◽

2016 ◽

Vol 114 (1) ◽

pp. E95-E104 ◽

Cited By ~ 25

Author(s):

Eugene Drokhlyansky ◽

Didem Göz Aytürk ◽

Timothy K. Soh ◽

Ryan Chrenek ◽

Elaine O’Loughlin ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Type I Interferon ◽

Brain Parenchyma ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Virus Spread ◽

Viral Spread ◽

The Brain

The brain has a tightly regulated environment that protects neurons and limits inflammation, designated “immune privilege.” However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate–putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.

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Defining the Immune Responses for SARS-CoV-2-Human Macrophage Interactions

10.1101/2021.07.07.449660 ◽

2021 ◽

Author(s):

Mai Mostafa ◽

Pravin Yeapuri ◽

Jatin Machhi ◽

Katherine Olson ◽

Farah Shahjin ◽

...

Keyword(s):

Immune Response ◽

Viral Infection ◽

Innate Immune Response ◽

Human Monocyte ◽

Innate Immune ◽

Mononuclear Phagocytes ◽

Human Macrophage ◽

Type I ◽

Innate Immune Signaling ◽

Organ Tissue

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end organ malfunctions. All follow an abortive viral infection. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding consequent end-organ tissue damage.

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MicroRNA as Type I Interferon-Regulated Transcripts and Modulators of the Innate Immune Response

Frontiers in Immunology ◽

10.3389/fimmu.2015.00334 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 73

Author(s):

Samuel C. Forster ◽

Michelle D. Tate ◽

Paul J. Hertzog

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Type I Interferon ◽

Innate Immune ◽

Type I

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Japanese Encephalitis Virus NS5 Inhibits Type I Interferon (IFN) Production by Blocking the Nuclear Translocation of IFN Regulatory Factor 3 and NF-κB

Journal of Virology ◽

10.1128/jvi.00039-17 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 31

Author(s):

Jing Ye ◽

Zheng Chen ◽

Yunchuan Li ◽

Zikai Zhao ◽

Wen He ◽

...

Keyword(s):

Immune Response ◽

Japanese Encephalitis Virus ◽

Innate Immune Response ◽

Nuclear Translocation ◽

Type I Interferon ◽

Transport Proteins ◽

Innate Immune ◽

Type I ◽

Regulatory Factor ◽

Host Innate Immune Response

ABSTRACT The type I interferon (IFN) response is part of the first-line defense against viral infection. To initiate replication, viruses have developed powerful evasion strategies to counteract host IFN responses. In the present study, we found that the Japanese encephalitis virus (JEV) NS5 protein could inhibit double-stranded RNA (dsRNA)-induced IFN-β expression in a dose-dependent manner. Our data further demonstrated that JEV NS5 suppressed the activation of the IFN transcriptional factors IFN regulatory factor 3 (IRF3) and NF-κB. However, there was no defect in the phosphorylation of IRF3 and degradation of IκB, an upstream inhibitor of NF-κB, upon NS5 expression, indicating a direct inhibition of the nuclear localization of IRF3 and NF-κB by NS5. Mechanistically, NS5 was shown to interact with the nuclear transport proteins KPNA2, KPNA3, and KPNA4, which competitively blocked the interaction of KPNA3 and KPNA4 with their cargo molecules, IRF3 and p65, a subunit of NF-κB, and thus inhibited the nuclear translocation of IRF3 and NF-κB. Furthermore, overexpression of KPNA3 and KPNA4 restored the activity of IRF3 and NF-κB and increased the production of IFN-β in NS5-expressing or JEV-infected cells. Additionally, an upregulated replication level of JEV was shown upon KPNA3 or KPNA4 overexpression. These results suggest that JEV NS5 inhibits the induction of type I IFN by targeting KPNA3 and KPNA4. IMPORTANCE JEV is the major cause of viral encephalitis in South and Southeast Asia, with high mortality. However, the molecular mechanisms contributing to the severe pathogenesis are poorly understood. The ability of JEV to counteract the host innate immune response is potentially one of the mechanisms responsible for JEV virulence. Here we demonstrate the ability of JEV NS5 to interfere with the dsRNA-induced nuclear translocation of IRF3 and NF-κB by competitively inhibiting the interaction of IRF3 and NF-κB with nuclear transport proteins. Via this mechanism, JEV NS5 suppresses the induction of type I IFN and the antiviral response in host cells. These findings reveal a novel strategy for JEV to escape the host innate immune response and provide new insights into the pathogenesis of JEV.

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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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RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production

Journal of Virology ◽

10.1128/jvi.00643-14 ◽

2014 ◽

Vol 88 (14) ◽

pp. 7987-7997 ◽

Cited By ~ 17

Author(s):

Jun Feng ◽

Paul D. De Jesus ◽

Victoria Su ◽

Stephanie Han ◽

Danyang Gong ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Type I Interferon ◽

Adaptor Protein ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Antiviral Responses ◽

Interferon Pathway ◽

Irf3 Activation

ABSTRACTDetection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3.IMPORTANCEThe innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.

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Faculty Opinions recommendation of Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.

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

10.3410/f.1113044.575002 ◽

2008 ◽

Author(s):

Achsah Keegan

Keyword(s):

Immune Response ◽

Viral Infection ◽

Lung Disease ◽

Innate Immune Response ◽

Chronic Lung Disease ◽

Innate Immune ◽

Respiratory Viral Infection

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Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes

Journal of Experimental Medicine ◽

10.1084/jem.20060045 ◽

2006 ◽

Vol 203 (4) ◽

pp. 933-940 ◽

Cited By ~ 99

Author(s):

Javier A. Carrero ◽

Boris Calderon ◽

Emil R. Unanue

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Innate Immune Response ◽

Early Stage ◽

Bacterial Pathogen ◽

Interleukin 10 ◽

Innate Immune ◽

Type I ◽

Phagocytic Cells ◽

Immunodeficient Mice

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor–deficient (IFN-αβR−/−) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-αβR+/+. The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection.

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