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Impact of species-specific host responses on restriction of hepatotropic viruses

物种特异性宿主反应对嗜肝病毒限制的影响

基本信息

批准号：
9104080
负责人：
Alexander Ploss
金额：
$ 24.86万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104080
关键词：
Affect Amino Acid Sequence Animal Model Antiviral Agents Antiviral Response Biology Biomedical Research Blood Borneo CD81 gene Cell Line Cell physiology Cells Cercopithecus pygerythrus Cessation of life Chronic Cirrhosis Clinical Collection Communicable Diseases Communities Cytochrome P450 Data Dermal Development Disease Exhibits Family member Fibroblasts Fibrosis Flavivirus Fluorescence Frequencies Generations Gorilla gorilla HCV Animal Models Health Hepatitis B Hepatitis B Virus Hepatitis C Hepatitis C virus Hepatitis Viruses Hepatocyte Human Immune response Infection Integration Host Factors Investigation Japanese Population Kinetics Lead Life Cycle Stages Light Liver Liver diseases Macaca mulatta Malignant neoplasm of liver Mus Orthologous Gene Outcome Pan Genus Pan paniscus Pan troglodytes Papio Pathway interactions Pattern Persons Plague Pluripotent Stem Cells Pongidae Pongo Pongo pygmaeus Predisposition Primary carcinoma of the liver cells Primates Publishing RNA Viruses RNA replication Reporter Research Personnel Resistance Rodent Role Serum Proteins Shapes Signal Transduction Skin Specimen Stem cells System Tissues Tropism Viral Virus Virus Assembly Virus Diseases Virus Replication Work antiviral immunity clinically relevant gene product human morbidity human mortality improved induced pluripotent stem cell insight interest laser capture microdissection nonhuman primate novel occludin pathogen permissiveness repository response species difference success transcriptomics uptake viral RNA virology

项目摘要

DESCRIPTION (provided by applicant): Infectious diseases contribute significantly to human morbidity and mortality. Many pathogens that cause disease in humans, exhibit a very narrow host range, which poses challenges both for study and for developing effective clinical therapies. We will focus our studies on hepatitis C virus (HCV), an archetypal hepatotropic virus with a narrow host range and derive cell-intrinsic immune response patterns that impact infection outcome across species. Eighty percent of HCV infections result in chronic infection and can lead to cirrhosis and hepatocellular carcinoma. HCV has an incompletely defined host tropism limited almost exclusively to humans and chimpanzees. We have previously demonstrated that differences (between human and mouse) between the amino acid sequences of two host factors, CD81 and occludin (OCLN) block HCV uptake in mice. While HCV assembly and release is supported in hepatocytes across a broad variety of species ranging from humans to rodents, antiviral innate responses appear to limit HCV RNA replication in non-human species. We hypothesize that species-specific differences in the kinetics, diversity and magnitude of antiviral gene products influence viral tropism. Here, we propose to develop and utilize a novel platform to systematically define such species-specific response patterns contributing to infection outcome. We aim to capitalize on a collection of dermal fibroblasts from non-human primate species to generate induced pluripotent stem cells (iPSCs) and differentiate these simian iPSCs in a stepwise manner to hepatocyte like cells (HLCs). We will characterize and compare viral infections in HLCs derived from human, chimpanzee, bonobo, gorilla, orangutan and rhesus monkey specimens. Orthologs of essential host factors critical for supporting the viral life-cycle are largely conserved across these species and differences in susceptibility can likely be attributed to differences in antiviral response patterns and/or HCV's inability to antagonize cell-intrinsic defenses. We will couple a HCV infection-dependent fluorescence relocalization (HDFR) reporter with laser capture microdissection (LCM) to isolate infected cells from HCV infected HLCs from different species and subject them to transcriptomic profiling. By comparing and contrasting data from species with high and low infection frequencies, we will be able to determine species-specific signatures associated with effective antiviral control. The success of this collaborative project depends on the complementary expertise in HCV virology and viral tropism (Ploss lab) and stem cell and hepatocyte biology (Schwartz lab). We are convinced that this systems virology approach will provide rich insights into evolutionary conservation of antiviral response patterns and shed light on the impact of antiviral immunity to restrict species tropism. Since many of the primate species for which we collect materials are endangered and cannot be used (anymore) in biomedical research, the emerging iPSC repository we will build will also be an enabling platform for other researchers needing access to usually inaccessible primate species/tissues.