The Role of TRIM6 and Ubiquitin in Influenza Virus-Induced Pathology

TRIM6 和泛素在流感病毒诱发的病理学中的作用

• 批准号: 10296160
• 负责人: Ricardo Rajsbaum
• 金额: $ 46.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-13 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296160
• 关键词: Affect; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; Biological Testing; Bone Marrow; CXCL1 gene; Cell membrane; Cells; Cessation of life; Chemotactic Factors; Chimera organism; Co-Immunoprecipitations; Complex; Coronavirus; Cytokine Signaling; Dangerousness; Data; Development; Disease; Epidemic; Equilibrium; Flow Cytometry; Future; Goals; IL8 gene; Immune; Impairment; Infection; Inflammation; Inflammatory; Influenza A virus; Interferon Type I; Interferons; Intervention; Knockout Mice; Knowledge; Learning; Lung; Lung Inflammation; Mediating; Molecular; Morbidity - disease rate; Mus; Mutation; Neutrophil Infiltration; Outcome; PI3K/AKT; Pathogenicity; Pathology; Pathway interactions; Pharmacology; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Polyubiquitin; Production; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Role; Signal Induction; Signal Transduction; Source; System; TNF gene; TNFRSF1A gene; Time; Tissues; Ubiquitin; Ubiquitination; Virus; Virus Diseases; Work; arm; base; cell type; chemokine; cytokine; improved; in vitro Assay; in vivo; influenzavirus; inhibitor/antagonist; innate immune mechanisms; monocyte; mortality; neutrophil; next generation sequencing; novel; novel therapeutic intervention; pandemic disease; public health relevance; receptor; recruit; response; single-cell RNA sequencing; targeted treatment; therapeutic development; tool; ubiquitin-protein ligase

ABSTRACT. Influenza A virus (IAV) causes annual epidemics and dangerous pandemics involving millions of cases of illness and deaths worldwide. The main cause of pathology from IAV is excessive inflammation, therefore, the overarching goal of this proposal is to learn how mechanisms of inflammation can be manipulated to promote disease tolerance to virus infection. Cytokine production, a chief contributor of inflammation, is regulated at the post-translational level to balance between efficient antiviral responses and damaging inflammation. A major molecular regulatory mechanism involves ubiquitination of signaling components. The specific goal of this proposal is to identify mechanisms of regulation of inflammation by the ubiquitin (Ub) system during IAV infection in vivo. We recently reported that the E3-Ub ligase, TRIM6, catalyzes the synthesis of unanchored poly-Ub chains, which promote antiviral IFN-I responses. However, the role of TRIM6 in regulating other inflammatory cytokines is not known. We generated TRIM6 knockout mice (Trim6-/-), which provides a unique tool to identify novel immune pathways regulated by TRIM6 and unanchored Ub in vivo. Our preliminary data show that Trim6-/- mice have fewer signs of pathology even though there are increased IAV titers at early time points post-infection. We also found reduced expression levels of CXCL1, a well-known neutrophil chemo-attractant, which correlated with reduced neutrophil infiltration to the lungs of IAV-infected Trim6-/- mice. We found that TRIM6 and unanchored Ub form a complex with PI3K/AKT signaling components, and their phosphorylation is impaired in Trim6-/- cells. Our data also suggest that TNFα produced by infected cells induces pathogenic CXCL1 in bystander cells to recruit neutrophils. Neutrophils are known to be recruited to the lung during IAV infection and can play both protective and detrimental roles. However, what factors drive neutrophils to cause tissue damage during infection are not well-understood. Therefore, there is a gap in knowledge on the mechanisms of regulation of neutrophil recruitment and their roles in the balance between protective responses and pathogenic inflammation. Our hypothesis is that TRIM6 is activated by TNFα signaling and promotes early CXCL1-mediated pathogenic inflammation, thereby inhibiting disease tolerance. In Aim 1, we will determine the cellular source of TRIM6-induced CXCL1, and its role in neutrophil recruitment to the lungs, during IAV infection. We will demonstrate the role of early CXCL1 production in pathology and whether TNFα is involved in inducing TRIM6-mediated CXCL1. In Aim 2, we will determine the mechanism by which TRIM6 and Ub modulate the activation of PI3K-AKT for downstream signaling and how TRIM6 is activated during infection. The outcomes include the identification of the cellular source of pathogenic CXCL1, and the mechanism by which TRIM6 is activated for signaling. This information will guide the development of therapeutic approaches by targeting TRIM6 and CXCL1-producing cells to reduce inflammatory diseases.

摘要。甲型流感病毒（IAV）每年引起流行病和危险的流行病，涉及数百万人