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Reverse Genetics Reveals a Role of Rotavirus VP3 Phosphodiesterase Activity in Inhibiting RNase L Signaling and Contributing to Intestinal Viral Replication In Vivo

文献类型： 外文期刊

作者： Song, Yanhua 1 ; Feng, Ningguo 1 ; Sanchez-Tacuba, Liliana 1 ; Yasukawa, Linda L. 1 ; Ren, Lili 5 ; Silverman, Robe 1 ;

作者机构： 1.Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA

2.Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA

3.VA Palo Alto Hlth Care Syst, Palo Alto Vet Inst Res, Palo Alto, CA 94304 USA

4.Jiangsu Acad Agr Sci, Inst Vet Med, Nanjing, Peoples R China

5.Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Peoples R China

6.Cleveland Clin, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44106 USA

7.Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA

关键词： gastrointestinal infection; innate immunity; interferons; rotavirus; virus-host interactions

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.103； 五年影响因子：5.078 ）

ISSN： 0022-538X

年卷期： 2020 年 94 卷 9 期

页码：

收录情况： SCI

摘要： Our understanding of how rotavirus (RV) subverts host innate immune signaling has greatly increased over the past decade. However, the relative contribution of each virus-encoded innate immune antagonist has not been fully studied in the context of RV infection in vivo. Here, we present both in vitro and in vivo evidence that the host interferon (IFN)-inducible 2'-5'-oligoadenylate synthetase (OAS) and RNase L pathway effectively suppresses the replication of heterologous RV strains. VP3 from homologous RVs relies on its 2'-5'-phosphodiesterase (PDE) domain to counteract RNase L-mediated antiviral signaling. Using an RV reversegenetics system, we show that compared to the parental strain, VP3 PDE mutant RVs replicated at low levels in the small intestine and were shed less in the feces of wild-type mice, and such defects were rescued in Rnasel(-/-) suckling mice. Collectively, these findings highlight an important role of VP3 in promoting viral replication and pathogenesis in vivo in addition to its well-characterized function as the viral RNA-capping enzyme. IMPORTANCE Rotaviruses are significant human pathogens that result in diarrhea, dehydration, and deaths in many children around the world. Rotavirus vaccines have suboptimal efficacy in low- to middle-income countries, where the burden of the diseases is the most severe. With the ultimate goal of improving current vaccines, we aim to better understand how rotavirus interacts with the host innate immune system in the small intestine. Here, we demonstrate that interferon-activated RNase L signaling blocks rotavirus replication in a strain-specific manner. In addition, virus-encoded VP3 antagonizes RNase L activity both in vitro and in vivo. These studies highlight an ever-evolving arms race between antiviral factors and viral pathogens and provide a new means of targeted attenuation for next-generation rotavirus vaccine design.

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