Regulation of Rotavirus Replication, Virulence, and Host Range Restriction by the Innate Immune System

先天免疫系统对轮状病毒复制、毒力和宿主范围限制的调节

• 批准号: 10091389
• 负责人: Harry Bernard Greenberg
• 金额: $ 47.16万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091389
• 关键词: Adaptor Signaling Protein; Address; Animals; Antiviral Agents; Area; Biological Assay; Biological Models; Biology; Bystander Effect; Cells; Chemicals; Child; Communicable Diseases; Complex; Cryoelectron Microscopy; Cullin Proteins; Data; Down-Regulation; Enteral; Enzymes; Epithelial Cells; Gastroenteritis; Hematopoietic; Human; IRF3 gene; Immune Evasion; Impairment; In Vitro; Innate Immune Response; Innate Immune System; Interferon Receptor; Interferons; Intestines; Mediating; Mitochondria; Mitochondrial Proteins; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Mutagenesis; Natural Immunity; Pathogenesis; Pattern; Phase; Phosphorylation; Prevention; Production; Protein Inhibition; Proteins; RNA Caps; Receptor Gene; Receptor Inhibition; Regulation; Research; Role; Rotavirus; Rotavirus Infections; Rotavirus NSP1 protein; SH2D3A gene; STAT1 gene; Signal Transduction; Signaling Protein; Small Interfering RNA; Structure; System; TBK1 gene; Ubiquitination; Vaccines; Viral; Viral Proteins; Virulence; Virulent; Virus; beta-Transducin Repeat-Containing Proteins; cullin-3; diarrheal disease; enteric pathogen; gastrointestinal; in vivo; in vivo Model; intestinal epithelium; knock-down; non-Native; pathogen; pathogenic virus; protein degradation; receptor; response; sensor; success; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Rotaviruses (RVs) are highly infectious viruses of great importance because they are the most common cause of severe gastroenteritis in young children. We will address three fundamental topics in rotavirology (RV) that will expand our understanding of the molecular mechanisms regulating RV innate immune evasion. 1. Determine the structural basis and in vivo activity of NSP1-mediated β-TrCP degradation. Despite the RV NSP1 protein's well-documented ability to induce IRF3 and/or β-TrCP degradation, the mechanisms regulating this degradation are unknown. Human RV NSP1s specifically target β-TrCP. We have recently identified an unexpected role of the host Cullin-E3 ligase complex in NSP1's degradative functions. In this aim we will dissect how NSP1 is able to hijack the host Cullin-E3 ligase complex, induce β- TrCP degradation, block NF-κB activation and thereby promote homologous RV replication. 2. Identify the molecular mechanisms underlying MAVS degradation by VP3 in a strain- and host- specific fashion both in vitro and in vivo. We previously showed that ssRNA byproducts from RV infection are potent activators of cytosolic sensors RIG-I and MDA5, both of which converge on mitochondrial antiviral signaling protein (MAVS) to relay innate signaling and induce IFN expression. Unexpected preliminary findings suggest that MAVS is targeted for proteasomal degradation by the RV VP3 protein in a host range restricted (HRR) manner. Here we will explore the complex interplay between VP3 and MAVS from different RV species at a mechanistic level and evaluate the importance of VP3-mediated MAVS degradation in promoting RV replication in vitro and in vivo. 3. Identify the mechanism of RV NSP1-mediated inhibition of STAT1 activation and the intestinal cell origin of the IFN responses to RV infection. Despite the ability to efficiently suppress the induction of type I IFN in intestinal epithelial cells (IECs), homologous RV infection still induces substantial levels of type I and III IFNs in the gut. This IFN production suggests that RVs must be able to subvert IFN-mediated antiviral amplification as well as blocking IFN induction. RV NSP1 efficiently inhibits IFN-mediated STAT1 phosphorylation. New findings indicate RV blocks STAT1 activation by depleting multiple IFN receptors, likely by NSP1-directed degradation. RVs can also block IFN-directed STAT1 activation in uninfected cells in vitro. Whether this effect also occurs in vivo is unknown. We propose to identify the hematopoietic cell and IEC origins of type I and III IFNs elicited by RV infection. We will also examine the mechanistic determinants of RV-mediated IFN receptor degradation and inhibition of STAT1 activation and determine if differences in these functions contribute to RV HRR.

项目总结/文摘

项目成果

Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells.

• DOI: 10.7554/elife.39494
• 发表时间: 2018-11-21
• 期刊: eLife
• 影响因子: 7.7
• 作者: Ding S;Zhu S;Ren L;Feng N;Song Y;Ge X;Li B;Flavell RA;Greenberg HB
• 通讯作者: Greenberg HB

STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection.

• DOI: 10.1038/s41467-018-03782-z
• 发表时间: 2018-04-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ding S;Diep J;Feng N;Ren L;Li B;Ooi YS;Wang X;Brulois KF;Yasukawa LL;Li X;Kuo CJ;Solomon DA;Carette JE;Greenberg HB
• 通讯作者: Greenberg HB

VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans.

• DOI: 10.1126/scitranslmed.aam5434
• 发表时间: 2017-06-21
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Nair N;Feng N;Blum LK;Sanyal M;Ding S;Jiang B;Sen A;Morton JM;He XS;Robinson WH;Greenberg HB
• 通讯作者: Greenberg HB