Author response: IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

AbstractMelanoma differentiation-associated gene-5 (MDA5) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates type I interferon (IFN) signaling and antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS and activation of TBK1 and IKK, subsequently leading to IRF3 and NF-κB phosphorylation. Great numbers of symptomatic and severe infections of SARS-CoV-2 are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral agents indicates that SARS-CoV-2 escapes from antiviral immune responses via an unknown mechanism. Here, we report that SARS-CoV-2 nonstructural protein 8 (NSP8) acts as an innate immune suppressor and inhibits type I IFN signaling to promote infection of RNA viruses. It downregulates the expression of type I IFNs, IFN-stimulated genes and proinflammatory cytokines by binding to MDA5 and impairing its K63-linked polyubiquitination. Our findings reveal that NSP8 mediates innate immune evasion during SARS-CoV-2 infection and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases.ImportanceThe large-scale spread of COVID-19 is causing mass casualties worldwide, and the failure of antiviral immune treatment suggests immune evasion. It has been reported that several nonstructural proteins of severe coronaviruses suppress antiviral immune responses; however, the immune suppression mechanism of SARS-CoV-2 remains unknown. Here, we revealed that NSP8 protein of SARS-CoV-2 directly blocks the activation of the cytosolic viral dsRNA sensor MDA5 and significantly downregulates antiviral immune responses. Our study contributes to our understanding of the direct immune evasion mechanism of SARS-CoV-2 by showing that NSP8 suppresses the most upstream sensor of innate immune responses involved in the recognition of viral dsRNA.

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Abstract 291: The Type I Interferon Receptor Amplifies Innate Immune Responses After Myocardial Infarction

Circulation Research ◽

10.1161/res.123.suppl_1.291 ◽

2018 ◽

Vol 123 (Suppl_1) ◽

Author(s):

Richard P Ng ◽

Kevin R King ◽

Aaron D Aguirre ◽

Sean P Arlauckas ◽

Ralph Weissleder

Keyword(s):

Myocardial Infarction ◽

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Interferon Receptor

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Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

Cell Death Discovery ◽

10.1038/s41420-021-00487-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

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IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

eLife ◽

10.7554/elife.45501 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Rosanne Spolski ◽

Erin E West ◽

Peng Li ◽

Sharon Veenbergen ◽

Sunny Yung ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Type I Interferon ◽

Human Peripheral Blood ◽

Granzyme B ◽

Gene Signature ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Wild Type ◽

Blood Neutrophils

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNβ induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.

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N6-methyladenosine modification of HIV-1 RNA evades RIG-I-mediated sensing to suppresses type-I interferon induction in monocytic cells

10.1101/2020.11.04.368712 ◽

2020 ◽

Author(s):

Shuliang Chen ◽

Sameer Kumar ◽

Nagaraja Tirumuru ◽

Jennifer L. Welch ◽

Lulu Hu ◽

...

Keyword(s):

Immune Responses ◽

Mononuclear Cells ◽

Type I Interferon ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Peripheral Blood Mononuclear ◽

Monocytic Cells ◽

Blood Mononuclear Cells ◽

Hiv 1

AbstractN6-methyladenosine (m6A) is a prevalent RNA modification that plays a key role in regulating eukaryotic cellular mRNA functions. RNA m6A modification is regulated by two groups of cellular proteins, writers and erasers that add or remove m6A, respectively. HIV-1 RNA contains m6A modifications that modulate viral infection and gene expression in cells. However, it remains unclear whether m6A modifications of HIV-1 RNA modulate innate immune responses in cells or HIV-1-infected individuals. Here we show that m6A modification of HIV-1 RNA suppresses the expression of antiviral cytokine type-I interferon (IFN-I) in human monocytic cells. Transfection of differentiated monocytic cells with HIV-1 RNA fragments containing a single m6A-modification significantly reduced IFN-I mRNA expression relative to their unmodified RNA counterparts. We generated HIV-1 with altered RNA m6A levels by manipulating the expression of the m6A erasers or pharmacological inhibition of m6A addition in virus-producing cells. RNA transfection and viral infection of differentiated monocytic cells demonstrated that HIV-1 RNA with decreased m6A levels enhanced IFN-I expression, whereas HIV-1 RNA with increased m6A modifications had opposite effects. Our mechanistic studies revealed that m6A of HIV-1 RNA escaped the RIG-I-mediated RNA sensing and activation of the transcription factors IRF3 and IRF7 that drive IFN-I gene expression. Moreover, RNA of peripheral blood mononuclear cells from HIV-1 viremic patients showed increased m6A levels that correlated with increased IFN-I mRNA expression compared to levels from HIV-1-suppressed patients on antiretroviral therapy. Together, our results suggest that RNA m6A modifications regulate viral replication and antiviral innate immune responses in HIV-1-infected individuals.Author SummaryHIV-1 is known as a weak inducer of antiviral cytokines including IFN-I, but it is unclear how HIV-1 evades innate immunity. Different types of RNA modifications including m6A within the HIV-1 genome modulate viral replication; however, the role of m6A modifications of HIV-1 RNA in regulating innate immune responses remains elusive. In this study, we found that HIV-1 RNA modified with m6A suppresses the expression of IFN-I in differentiated monocytic cells by avoiding innate immune detection of viral RNA mediated by RIG-I, an RNA sensor in host cells. We also observed significantly increased RNA m6A modifications of peripheral blood mononuclear cells from HIV-1 viremic patients compared to virally suppressed patients on combined antiretroviral therapy, suggesting a functional link between m6A modifications and antiretroviral treatment. Investigating the functions of m6A modifications of HIV-1 RNA in regulating innate immune sensing and IFN-I induction in monocytic cells can help understand the mechanisms of HIV-1 persistence.

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ALG2 regulates type I interferon responses by inhibiting STING trafficking

Journal of Cell Science ◽

10.1242/jcs.259060 ◽

2021 ◽

Author(s):

Wangsheng Ji ◽

Lianfei Zhang ◽

Xiaoyu Xu ◽

Xinqi Liu

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Innate Immune Responses ◽

Downstream Signaling ◽

Interferon Responses ◽

Hsv 1

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

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Enterovirus D68 Protease 2Apro Targets TRAF3 to Subvert Host Innate Immune Responses

Journal of Virology ◽

10.1128/jvi.01856-20 ◽

2020 ◽

Author(s):

Jun Kang ◽

Zheng Pang ◽

Zhenwei Zhou ◽

Xianhuang Li ◽

Sihua Liu ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Nonstructural Protein ◽

Tumor Necrosis Factor Receptor ◽

Innate Immune ◽

Human Enterovirus ◽

Type I ◽

Innate Immune Responses ◽

Acute Flaccid Myelitis ◽

Tract Infections

Human enterovirus 68 (EV-D68) has received considerable attention recently as a global re-emergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis (AFM). The nonstructural protein 2A protease (2Apro) of EVs that function in the cleavage of host proteins comprises a pivotal part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. In this study, we found EV-D68 inhibited anti-viral type I interferon responses by cleaving tumor necrosis factor receptor associated factor 3 (TRAF3), which is the key factor for type I interferon production. EV-D68 inhibited Sendai virus (SEV)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression in HeLa and HEK293T cells. Furthermore, we demonstrated that EV-D68 and 2Apro was able to cleave the C-terminal region of TRAF3 in HeLa and HEK293T cells, respectively. A cysteine to alanine substitution at amino acid 107 (C107A) in the 2Apro protease resulted in the loss of cleavage activity to TRAF3, and mutation of glycine at amino acid 462 to alanine (G462A) in TRAF3 conferred resistance to 2Apro. These results suggest that control of TRAF3 by 2Apro may be a mechanism EV-D68 utilizes to subvert host innate immune responses. IMPORTANCE Human enterovirus 68 (EV-D68) has received considerable attention recently as a global re-emergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis. The nonstructural protein 2A protease (2Apro) of EV, which functions in cleavage of host proteins, comprises an essential part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. Here, we show for the first time that EV-D68 inhibited anti-viral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3). Furthermore, we identified the key cleavage site in TRAF3. Our study may suggest a new mechanism by which the 2Apro of EV facilitates subversion of host innate immune responses. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets against EV-D68.

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The Intestinal Microbiome Primes Host Innate Immunity against Enteric Virus Systemic Infection through Type I Interferon

mBio ◽

10.1128/mbio.00366-21 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Xiao-Lian Yang ◽

Gan Wang ◽

Jin-Yan Xie ◽

Han Li ◽

Shu-Xian Chen ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Type I Interferon ◽

Systemic Infection ◽

Enteric Virus ◽

Innate Immune ◽

Commensal Bacteria ◽

Type I ◽

Innate Immune Responses ◽

Host Innate Immunity

ABSTRACT Intestinal microbiomes are of vital importance in antagonizing systemic viral infection. However, very little literature has shown whether commensal bacteria play a crucial role in protecting against enteric virus systemic infection from the aspect of modulating host innate immunity. In the present study, we utilized an enteric virus, encephalomyocarditis virus (EMCV), to inoculate mice treated with phosphate-buffered saline (PBS) or given an antibiotic cocktail (Abx) orally or intraperitoneally to examine the impact of microbiota depletion on virulence and viral replication in vivo. Microbiota depletion exacerbated the mortality, neuropathogenesis, viremia, and viral burden in brains following EMCV infection. Furthermore, Abx-treated mice exhibited severely diminished mononuclear phagocyte activation and impaired type I interferon (IFN) production and expression of IFN-stimulated genes (ISG) in peripheral blood mononuclear cells (PBMC), spleens, and brains. With the help of fecal bacterial 16S rRNA sequencing of PBS- and Abx-treated mice, we identified a single commensal bacterium, Blautia coccoides, that can restore mononuclear phagocyte- and IFNAR (IFN-α/β receptor)-dependent type I IFN responses to restrict systemic enteric virus infection. These findings may provide insight into the development of novel therapeutics for preventing enteric virus infection or possibly alleviating clinical diseases by activating host systemic innate immune responses via respective probiotic treatment using B. coccoides. IMPORTANCE While cumulative data indicate that indigenous commensal bacteria can facilitate enteric virus infection, little is known regarding whether intestinal microbes have a protective role in antagonizing enteric systemic infection by modulating host innate immunity. Although accumulating literature has pointed out that the microbiota has a fundamental impact on host systemic antiviral innate immune responses mediated by type I interferon (IFN), only a few specific commensal bacteria species have been revealed to be capable of regulating IFN-I and ISG expression, not to mention the underlying mechanisms. Thus, it is important to understand the cross talk between microbiota and host anti-enteric virus innate immune responses and characterize the specific bacterial species that possess protective functions. Our study demonstrates how fundamental innate immune mediators such as mononuclear phagocytes and type I IFN are regulated by commensal bacteria to antagonize enteric virus systemic infection. In particular, we have identified a novel commensal bacterium, Blautia coccoides, that can restrict enteric virus replication and neuropathogenesis by activating IFN-I and ISG responses in mononuclear phagocytes via an IFNAR- and STAT1-mediated signaling pathway.

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Caspase-Dependent Suppression of Type I Interferon Signaling Promotes Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

Journal of Virology ◽

10.1128/jvi.00078-18 ◽

2018 ◽

Vol 92 (10) ◽

pp. e00078-18 ◽

Cited By ~ 6

Author(s):

Tate Tabtieng ◽

Alexei Degterev ◽

Marta M. Gaglia

Keyword(s):

Immune Responses ◽

Viral Replication ◽

Kaposi's Sarcoma ◽

Type I Interferon ◽

Viral Gene Expression ◽

Kaposi’S Sarcoma ◽

Innate Immune ◽

Viral Gene ◽

Type I ◽

Innate Immune Responses

ABSTRACTAn important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic acids. Inhibition of type I IFN responses by the virus promotes viral replication. Here, we report that KSHV uses a caspase-dependent mechanism to block type I IFN, in particular IFN-β, responses during lytic infection. Inhibition of caspases during KSHV reactivation resulted in increased TBK1/IKKε-dependent phosphorylation of IRF3 as well as elevated levels of IFN-β transcription and secretion. The increased secretion of IFN-β upon caspase inhibition reduced viral gene expression, viral DNA replication, and virus production. Blocking IFN-β production or signaling restored viral replication. Overall, our results show that caspase-mediated regulation of pathogen sensing machinery is an important mechanism exploited by KSHV to evade innate immune responses.IMPORTANCEKSHV is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining tumor that is one of the most common causes of cancer death in sub-Saharan Africa. In this study, we examined the role of a set of cellular proteases, called caspases, in the regulation of immune responses during KSHV infection. We demonstrate that caspases prevent the induction and secretion of the antiviral factor IFN-β during replicative KSHV infection. The reduced IFN-β production allows for high viral gene expression and viral replication. Therefore, caspases are important for maintaining KSHV replication. Overall, our results suggest that KSHV utilizes caspases to evade innate immune responses, and that inhibiting caspases could boost the innate immune response to this pathogen and potentially be a new antiviral strategy.

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