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Probing the contribution of viral heterogeneity to interferon induction

探讨病毒异质性对干扰素诱导的贡献

基本信息

批准号：
9646221
负责人：
Alistair B Russell
金额：
$ 16.11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-20 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9646221
关键词：
Antiviral Agents Antiviral Response Behavior Behavioral Biological Assay Cell Line Cells Complement Complex Data Set Detection Disease Etiology Event Exhibits Failure Funding Generations Genetic Genetic Variation Genomic Segment Genotype Heterogeneity Human Human body Hybrids Immune Immune response Individual Infection Influenza Influenza A virus Influenza B Virus Innate Immune System Interferons Intrinsic factor Link Measurement Measures Mentors Mentorship Messenger RNA Modernization Mutation Natural Immunity Nature Orthomyxoviridae Pathogenicity Pathway interactions Pattern Phenotype Population Production Productivity RNA Viruses Reporter Resources Role Science Signaling Molecule Signaling Protein Source Stereotyping Techniques Therapeutic Intervention Time Training Variant Viral Viral Genome Virion Virus Virus Activation Virus Diseases Virus Replication Work bone combinatorial comparative cost deep sequencing experience fighting fitness genetic approach human morbidity human mortality innate immune pathways insight mutant pathogen pressure resilience response reverse genetics skills transcriptomics viral RNA virology

项目摘要

Project Summary Cell intrinsic innate immune pathways present a barrier that nearly all pathogens must overcome in order to successfully complete their infectious lifecycle. Influenza A virus (IAV) is no different, and engages several different strategies in order to evade or otherwise suppress recognition by the host. This is crucial to viral survival, as the production of interferons, the central signaling molecules of the innate response, results in the propagation of a highly antiviral state to which even IAV is susceptible. Regardless, IAV is still detected in a small subset of infected cells. In order to understand, and potentially manipulate, the host response to IAV, we must first understand the nature of those rare infections that propagate an interferon response. Does the incredible genetic and behavioral diversity exhibited in IAV infections predispose their recognition? And, if so, is there a single stereotyped pattern of immunostimulatory variation, or do multiple points of viral failure exist? Over the course of the two-year funding period, Dr. Russell will quantitatively measure how heterogeneity in IAV populations impacts their recognition by innate immune pathways. This will require sequencing bulk, infected, populations of cells as well as single-cell transcriptomic measurements – both of which have been developed and piloted by Dr. Russell while in Dr. Jesse Bloom's lab. Moving beyond the observational science enabled by these sequencing approaches, Dr. Russell will explore both newly- and previously-identified immunostimulatory IAV variation to establish causality. This will include attempts to ascertain whether all immunostimulatory variation acts through the same, shared, mechanisms. This will be primarily accomplished by recapitulating variation in pure viral populations using a reverse-genetic approach, permitting the independent exploration of individual sources of immunostimulatory heterogeneity. Lastly, Dr. Russell will seek to expand his work beyond IAV to a related virus of human importance, Influenza B virus. Comparisons across distinct viral lineages will provide vital insight into whether viral interactions with innate immunity are static over evolutionary time, or whether they are relatively dynamic and thus intractable to a generalizable therapeutic intervention. Overall, this work will generate a robust framework describing the totality of innate immune recognition of these viruses, serving as a substantial resource to the field moving forward.

项目总结