scholarly journals The Intestinal Microbiome Primes Host Innate Immunity Against Enteric Virus Systemic Infection Through Type I Interferon

2021 ◽  
Author(s):  
Xiao-Lian Yang ◽  
Gan Wang ◽  
Jin-Yan Xie ◽  
Han Li ◽  
Wei Liu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Type I Interferon ◽  
Systemic Infection ◽  
Enteric Virus ◽  
Encephalomyocarditis Virus ◽  
Commensal Bacteria ◽  
Intestinal Microbiome ◽  
Type I ◽  
Type I Ifn ◽  
Host Innate Immunity

Abstract BackgroundIntestinal 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 enteric virus systemic infection from the aspect of modulating host innate immunity. Also, only a few specific commensal bacteria species have been revealed to be capable in regulating antiviral innate immune responses mediated by type I interferon (IFN). The underlying mechanisms have not yet been elucidated.ResultsWe utilized an enteric virus, encephalomyocarditis virus (EMCV) to inoculate PBS-treated or antibiotic cocktail-administrated mice (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 brain following EMCV infection. Furthermore, Abx-treated mice exhibited severely diminished macrophage activation and impaired type I IFN production and ISG expression in PBMC, spleen or brain. With the help of fecal bacterial 16S rRNA sequencing of PBS and Abx mice, we identified a single commensal bacterium Blautia coccoides (B. coccoides) that can restore macrophage- and IFNAR-dependent type I IFN responses to restrict systemic enteric virus infection.ConclusionOur present study demonstrates that intestinal microbiome is fundamental for protecting from enteric virus systemic infection through activating macrophages and type I IFN responses. Reconstitution with B. coccoides can inhibit enteric virus infection and mitigate its neuropathogenesis by activating IFN-I and ISG responses in macrophages via IFNAR- and STAT1-mediated signaling pathway.

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

mBio ◽  
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.

scholarly journals PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Chuan Xia ◽  
Jennifer J. Wolf ◽  
Chuankai Sun ◽  
Mengqiong Xu ◽  
Caleb J. Studstill ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Influenza Virus ◽  
Molecular Mechanism ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Host Type ◽  
Host Innate Immunity

ABSTRACT Influenza A virus (IAV) utilizes multiple strategies to confront or evade host type I interferon (IFN)-mediated antiviral responses in order to enhance its own propagation within the host. One such strategy is to induce the degradation of type I IFN receptor 1 (IFNAR1) by utilizing viral hemagglutinin (HA). However, the molecular mechanism behind this process is poorly understood. Here, we report that a cellular protein, poly(ADP-ribose) polymerase 1 (PARP1), plays a critical role in mediating IAV HA-induced degradation of IFNAR1. We identified PARP1 as an interacting partner for IAV HA through mass spectrometry analysis. This interaction was confirmed by coimmunoprecipitation analyses. Furthermore, confocal fluorescence microscopy showed altered localization of endogenous PARP1 upon transient IAV HA expression or during IAV infection. Knockdown or inhibition of PARP1 rescued IFNAR1 levels upon IAV infection or HA expression, exemplifying the importance of PARP1 for IAV-induced reduction of IFNAR1. Notably, PARP1 was crucial for the robust replication of IAV, which was associated with regulation of the type I IFN receptor signaling pathway. These results indicate that PARP1 promotes IAV replication by controlling viral HA-induced degradation of host type I IFN receptor. Altogether, these findings provide novel insight into interactions between influenza virus and the host innate immune response and reveal a new function for PARP1 during influenza virus infection. IMPORTANCE Influenza A virus (IAV) infections cause seasonal and pandemic influenza outbreaks, which pose a devastating global health concern. Despite the availability of antivirals against influenza, new IAV strains continue to persist by overcoming the therapeutics. Therefore, much emphasis in the field is placed on identifying new therapeutic targets that can more effectively control influenza. IAV utilizes several tactics to evade host innate immunity, which include the evasion of antiviral type I interferon (IFN) responses. Degradation of type I IFN receptor (IFNAR) is one known method of subversion, but the molecular mechanism for IFNAR downregulation during IAV infection remains unclear. Here, we have found that a host protein, poly(ADP-ribose) polymerase 1 (PARP1), facilitates IFNAR degradation and accelerates IAV replication. The findings reveal a novel cellular target for the potential development of antivirals against influenza, as well as expand our base of knowledge regarding interactions between influenza and the host innate immunity.

scholarly journals Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Jintao Zhang ◽  
Chunyuan Zhao ◽  
Wei Zhao
Keyword(s):  
Innate Immunity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Responses ◽  
Public Health Challenges ◽  
Host Innate Immunity ◽  
Efficient Elimination

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.

scholarly journals TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity

2016 ◽  
Vol 214 (2) ◽  
pp. 459-473 ◽  
Author(s):  
Xueting Lang ◽  
Tiantian Tang ◽  
Tengchuan Jin ◽  
Chen Ding ◽  
Rongbin Zhou ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Signaling Pathways ◽  
Type I Interferon ◽  
Critical Role ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Interferon Signaling ◽  
Antiviral Innate Immunity ◽  
Irf3 Activation

MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)–induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid–inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65−/− mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.

scholarly journals Non-segmented negative-sense RNA viruses utilize N6-methyladenosine (m6A) as a common strategy to evade host innate immunity

2021 ◽  
Author(s):  
Mijia Lu ◽  
Miaoge Xue ◽  
Hai-Tao Wang ◽  
Elizabeth L. Kairis ◽  
Sadeem Ahmad ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Signaling Pathway ◽  
Type I Interferon ◽  
Rna Viruses ◽  
Viral Rna ◽  
Type I ◽  
Viral Rnas ◽  
Common Strategy ◽  
Host Innate Immunity ◽  
Negative Sense

N6-methyladenosine (m6A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m6A methylation in their RNAs. However, the biological functions of viral m6A methylation are poorly understood. Here, we found that viral m6A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m6A methylation is universally conserved in several families in non-segmented negative-sense (NNS) RNA viruses. Using m6A methyltransferase (METTL3)-knockout cells, we produced m6A-deficient virion RNA from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m6A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m6A-sufficient viral RNAs, in a RIG-I dependent manner. Reconstitution of the RIG-I pathway revealed that m6A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m6A binding protein YTHDF2 is essential for suppression of type I interferon signaling pathway included by virion RNA. Collectively, our results suggest that several families in NNS RNA viruses acquire m6A in viral RNA as a common strategy to evade host innate immunity. IMPORTANCE The non-segmented negative-sense (NNS) RNA viruses share many common replication and gene expression strategies. There is no vaccine or antiviral drugs for many of these viruses. We found that representative members in the families of Pneumoviridae, Paramyxoviridae, and Rhabdoviridae in NNS RNA viruses acquire m6A methylation in their genome and antigenome as a means to escape the recognition by host innate immunity via a RIG-I dependent signaling pathway. Viral RNA lacking m6A methylation induces a significantly higher type I interferon compared to m6A sufficient viral RNA. In addition to uncovering m6A methylation as a common mechanism for many NNS RNA viruses to evade host innate immunity, this study discovered a novel strategy to enhance type I interferon responses, which may have important applications in vaccine development, as a robust innate immunity will likely promote the subsequent adaptive immunity.

scholarly journals MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity

2021 ◽  
Author(s):  
Kamal U. Saikh
Keyword(s):  
Innate Immunity ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Adaptor Proteins ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Immune Signaling ◽  
Tir Domain ◽  
Host Innate Immunity

Abstract The continuous emergence of infectious pathogens along with antimicrobial resistance creates a need for an alternative approach to treat infectious diseases. Targeting host factor(s) which are critically involved in immune signaling pathways for modulation of host immunity offers to treat a broad range of infectious diseases. Upon pathogen-associated ligands binding to the Toll-like/ IL-1R family, and other cellular receptors, followed by recruitment of intracellular signaling adaptor proteins, primarily MyD88, trigger the innate immune responses. But activation of host innate immunity strongly depends on the correct function of MyD88 which is tightly regulated. Dysregulation of MyD88 may cause an imbalance that culminates to a wide range of inflammation-associated syndromes and diseases. Furthermore, recent reports also describe that MyD88 upregulation with many viral infections is linked to decreased antiviral type I IFN response, and MyD88-deficient mice showed an increase in survivability. These reports suggest that MyD88 is also negatively involved via MyD88-independent pathways of immune signaling for antiviral type I IFN response. Because of its expanding role in controlling host immune signaling pathways, MyD88 has been recognized as a potential drug target in a broader drug discovery paradigm. Targeting BB-loop of MyD88, small molecule inhibitors were designed by structure-based approach which by blocking TIR–TIR domain homo-dimerization have shown promising therapeutic efficacy in attenuating MyD88-mediated inflammatory impact, and increased antiviral type I IFN response in experimental mouse model of diseases. In this review, we highlight the reports on MyD88-linked immune response and MyD88-targeted therapeutic approach with underlying mechanisms for controlling inflammation and antiviral type I IFN response. Highlights • Host innate immunity is activated upon PAMPs binding to PRRs followed by immune signaling through TIR domain–containing adaptor proteins mainly MyD88. • Structure-based approach led to develop small-molecule inhibitors which block TIR domain homodimerization of MyD88 and showed therapeutic efficacy in limiting severe inflammation-associated impact in mice. • Therapeutic intervention of MyD88 also showed an increase in antiviral effect with strong type I IFN signaling linked to increased phosphorylation of IRFs via MyD88–independent pathway. • MyD88 inhibitors might be potentially useful as a small-molecule therapeutics for modulation of host immunity against inflammatory diseases and antiviral therapy. • However, prior clinical use of more in-depth efforts should be focused for suitability of the approach in deploying to complex diseases including COPD and COVID-19 in limiting inflammation-associated syndrome to infection.

scholarly journals Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joel M. J. Tan ◽  
Monica E. Garner ◽  
James M. Regeimbal ◽  
Catherine J. Greene ◽  
Jorge D. Rojas Márquez ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Transmembrane Protein ◽  
Foodborne Pathogen ◽  
Systemic Infection ◽  
Cytokine Signaling ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Protein

AbstractThe type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection. Mechanistically, type I IFN suppresses phagosome maturation and proteolysis of Lm virulence factors ActA and LLO, thereby promoting phagosome escape and cell-to-cell spread; the antiviral protein, IFN-induced transmembrane protein 3 (IFITM3), is required for this type I IFN-mediated alteration. Ifitm3−/− mice are resistant to systemic infection by Lm, displaying decreased bacterial spread in tissues, and increased immune cell recruitment and pro-inflammatory cytokine signaling. Together, our findings show how an antiviral mechanism in phagocytes can be exploited by bacterial pathogens, and implicate IFITM3 as a potential antimicrobial therapeutic target.

scholarly journals Investigation of type I interferon responses in ANCA-associated vasculitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isabella Batten ◽  
Mark W. Robinson ◽  
Arthur White ◽  
Cathal Walsh ◽  
Barbara Fazekas ◽  
...  
Keyword(s):  
Protein Expression ◽  
Type I Interferon ◽  
Contributory Factor ◽  
Type I ◽  
Healthy Controls ◽  
Type I Ifn ◽  
Serum Samples ◽  
Anca Associated Vasculitis ◽  
Clinical Measurements ◽  
Interferon Responses

AbstractType I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

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