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SAFA initiates innate immunity against cytoplasmic RNA virus SFTSV infection

ABSTRACT: Nuclear scaffold attachment factor A (SAFA) is a novel RNA sensor involved in sensing viral RNA in the nucleus and mediating antiviral immunity. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a bunyavirus that causes SFTS with a high fatality rate of up to 30%. It remains elusive whether and how cytoplasmic SFTSV can be sensed by the RNA sensor SAFA. Here, we demonstrated that SAFA was able to detect SFTSV infection and mediate antiviral interferon and inflammatory responses. Transcription and expression levels of SAFA were strikingly upregulated under SFTSV infection. SAFA was retained in the cytoplasm by interaction with SFTSV nucleocapsid protein (NP). Importantly, SFTSV genomic RNA was recognized by cytoplasmic SAFA, which recruited and promoted activation of the STING-TBK1 signaling axis against SFTSV infection. Of note, the nuclear localization signal (NLS) domain of SAFA was important for interaction with SFTSV NP and recognition of SFTSV RNA in the cytoplasm. In conclusion, our study reveals a novel antiviral mechanism in which SAFA functions as a novel cytoplasmic RNA sensor that directly recognizes RNA virus SFTSV and mediates an antiviral response. Author summary Severe fever with thrombocytopenia syndrome virus (SFTSV) is an RNA virus with a high fatality rate of up to 30%, which replicates exclusively in the cytoplasm. To date, many cytoplasmic RNA sensors were known to recognize SFTSV infection and trigger antiviral immune responses. Nuclear scaffold attachment factor A (SAFA) is a novel nuclear RNA sensor which can sense viral RNA in the nucleus and promote activation of antiviral immunity. However, there are no studies to investigate whether SAFA could detect cytoplasmic RNA virus infection. Here, we reported that SAFA was able to detect RNA virus SFTSV invasion. Under SFTSV infection, SAFA was retained in the cytoplasm and recognized SFTSV infection by interaction with SFTSV nucleocapsid protein (NP) and cytoplasmic SFTSV RNA directly. Importantly, SAFA recruited and promoted the activation of the STING-TBK1 signaling pathway-mediated antiviral immunity to suppress SFTSV infection. This study provides a further acquaintance in SAFA-mediated antiviral immune responses, illustrating the novel role of SAFA in sensing cytoplasmic SFTSV and mediates an antiviral response.

SUBMITTER: Liu B

PROVIDER: S-EPMC8598041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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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SAFA initiates innate immunity against cytoplasmic RNA virus SFTSV infection

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