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Identifying genetic barriers to animal virus replication in human cells: Insights into zoonosis

识别人类细胞中动物病毒复制的遗传障碍：深入了解人畜共患病

基本信息

批准号：
10794558
负责人：
Cody Jay Warren
金额：
$ 24.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10794558
关键词：
Address Animals Arterivirus Biological Blood Blood Circulation CRISPR screen Cells Clustered Regularly Interspaced Short Palindromic Repeats Complement Data Data Analyses Disease Dominant Genes Ebola virus Ecology Epidemic Face Family Genes Genetic Genomic approach Geographic Distribution Goals HIV-1 Health High-Throughput Nucleotide Sequencing Human Infection Integration Host Factors Interferons Investments Knock-out Macrophage Membrane Glycoproteins Metagenomics Middle East Respiratory Syndrome Coronavirus Molecular Evolution Monkeys Mutation Natural Immunity Natural Selections Natural experiment Nature Orthologous Gene Pathogenicity Phenotype Play Predisposition Primates Process Proteins Public Health Relative Risks Research Personnel Risk Role SARS coronavirus SIV Series Severe Acute Respiratory Syndrome Species Specificity Testing Training Viral Viral Load result Viral Proteins Virus Virus Diseases Virus Replication Work Writing Zoonoses antiviral immunity cDNA Library cofactor cross-species transmission functional genomics genome analysis genome sequencing genome-wide insight interest knock-down novel pandemic disease prevent prospective receptor receptor binding success tool transcription factor transmission process viral transmission virus host interaction

项目摘要

Project Summary Many emerging zoonotic viruses (animal viruses that transmit to humans) are highly pathogenic, having the potential to cause deadly epidemics or even global pandemics. The risks zoonotic viruses pose are highlighted by the emergence of the SARS/MERS coronaviruses, Ebola virus, and HIV-1, all of which are related to animal viruses that were unknown before they caused substantial cases of disease in humans. Given the risk animal viruses pose to humans, many researchers have turned to viral discovery—using genome sequencing tools and metagenomic analyses, researchers hope to identify novel animal viruses before they emerge in humans. While such efforts will prove invaluable to our understanding animal virus ecology, I seek to expand this work by experimentally evaluating the zoonotic risk an animal virus poses. The crux of this proposal is as follows. Experimental assessment of animal virus replication in human cells is crucial to evaluate zoonotic risk. However, an animal virus facing one block to replication in a human cell will have the same phenotype as an animal virus facing twenty blocks: producing low or no titers on human cells. But there is a critical difference between these two scenarios—an animal virus facing one block poses a greater zoonotic risk because it requires fewer adaptive mutations to replicate in human cells. Here, I propose to develop and demonstrate an experimental pipeline that will distinguish between animal viruses facing few blocks to replication in human cells from those with many. Host genetics plays a critical role in the species specificity of viruses. Divergence in host proteins used for virus entry (cellular receptors), replication (cellular cofactors), and antiviral immunity (restriction factors) can serve as potent barriers to virus infection in a new host species. Using hypothesis-driven studies and high- throughput genomic approaches, I will systematically characterize this host-virus interaction landscape for an understudied family of primate viruses (simarteriviruses). In Aim 1, I will assess the compatibility of diverse simarteriviruses with the human version of their cellular receptor, CD163. In Aim 2, I will employ a CRISPR screen to identify host cofactors required for simarterivirus replication. Then, I will use evolutionary signatures of positive natural selection to identify those host proteins likely to engage simarteriviruses in a species-specific manner. In Aim 3, I will identify antiviral proteins that block simarterivirus replication. Using a series of gene knockdowns and complementations, I will evaluate the genetic barriers to simarterivirus replication in human cells (Aims 1-3). Taken together, these aims will establish an experimental framework to evaluate the zoonotic risk of an understudied animal virus, and will provide me with new training in 1) performing and writing about molecular evolution analyses, 2) developing high-throughput sequencing projects and data analysis, and 3) functional genomics, defined as the execution and analysis of genome-scale screens for phenotypes of interest.

项目总结