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Determining mechanisms of innate immune modulation by ADP-ribosylation

通过 ADP-核糖基化确定先天免疫调节机制

基本信息

批准号：
10386112
负责人：
Anthony R Fehr
金额：
$ 3万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386112
关键词：
ADP Ribose Transferases ADP ribosylation Address Adenosine Diphosphate Ribose Affect Antiviral Agents Antiviral Response Antiviral Therapy Automobile Driving Biological Process Biology Cell Culture Techniques Cells Chiroptera Communicable Diseases Coronavirus Family Foundations Goals Hydrolase Hypersensitivity Immune response Impairment Infection Innate Immune Response Interferons Knock-out Knowledge Lead Malignant Neoplasms Mediating Mission Modeling Murine hepatitis virus National Institute of General Medical Sciences Pathway interactions Phenotype Phosphorylation Post-Translational Protein Processing Process Proteins RNA replication Research Research Personnel Role System Togaviridae Translations Viral Viral hepatitis Virus Virus Diseases Virus Replication Work human disease immunoregulation inhibitor/antagonist innate immune mechanisms innovation mutant novel pathogenic virus protein function response

项目摘要

PROJECT SUMMARY ADP-ribosylation is an important post-translational modification that directly influences several biological processes including cancer, allergy, and infectious disease. ADP-ribose can be added to proteins as one or more consecutive units by ADP-ribosyltransferases, also termed PARPs, resulting in mono- or poly- ADP-ribosylation (mAR or pAR). Most mARylating PARPs are upregulated by interferon (IFN) upon virus infection and several are predicted to have antiviral functions. In addition, several viral families, including the Coronaviridae and Togaviridae, encode for macrodomain proteins that have mono-ADP-ribosyl hydrolase (ARH) activity. This activity allows these viruses the ability to specifically counteract the effects of mAR, further implicating mAR in the mammalian antiviral response. Despite these findings, there are only a few known examples where mAR is known to inhibit virus replication. This is largely due to the lack of cell culture models of virus infections where the mAR status of a cell can be specifically controlled, such as models using mutant viruses or PARP knockout cells that have significant phenotypes. Importantly, the PI has established a virus infection system using a model coronavirus, Murine Hepatitis Virus (MHV), where virus lacking ARH activity is i) significantly impaired in virus replication and ii) independently induces a robust IFN response. These phenotypes are reversed by PARP inhibitors, establishing mAR as a key factor driving this anti-viral response. The investigator’s long-term goal is to determine mechanistically how mAR inhibits virus replication and enhances the innate immune response following virus infection. This gap in knowledge will be resolved by answering the following questions: 1) How does mAR inhibit MHV infection? Does it inhibit the entry, RNA replication, protein translation, assembly, or release of MHV? 2) What step(s) of the IFN induction pathway is enhanced by mAR, and does mAR also affect the IFN response in bats, which are known to harbor many highly pathogenic viruses? 3) What proteins are modified by PARPs following virus infection and which substrates are relevant for specific phenotypes? The rationale for this research is that it will enhance our understanding of mAR, including its ability to modulate protein function and will uncover novel cellular proteins or processes that mediate virus replication. The work is innovative because: i) it will bridge a significant knowledge gap between ADP-ribose biology, the innate immune response, and virus replication; ii) it utilizes unique models of infection utilizing both mutant viruses and PARP knockout cells; and iii) will be the first to address the role of mAR in bats. Finally, these projects are significant and relevant to the NIGMS mission because they will provide a thorough understanding of how mAR impacts the anti-viral response that could lay the foundation for advances in the treatment of virus infections or other human diseases impacted by mAR.

项目总结