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Viral and Host Determinants of Chikungunya Virus Dissemination

基孔肯雅病毒传播的病毒和宿主决定因素

基本信息

批准号：
10056971
负责人：
Kathryn Semmens Carpentier
金额：
$ 4.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056971
关键词：
Acute Acute Disease Alphavirus Americas Amino Acids Animal Model Antiviral Agents Arboviruses Arthralgia Arthritis Asia Biochemical Blood Circulation Cell Culture Techniques Cells Chikungunya virus Chronic Chronic Disease Culicidae Data Development Dichloromethylene Diphosphonate Disease Disease Outbreaks Disease Outcome Epidemic Europe Event Far East Fever Genetic Polymorphism Glycoproteins Human ITGAX gene Immune response Immunohistochemistry In Situ Hybridization Indian Ocean Individual Infection Innate Immune Response Integration Host Factors Interferon Type I Interferons Intravenous Knowledge Laboratories Link Liposomes Mediating Mouse Strains Mus Mutate Mutation O&apos nyong-nyong virus Pathogenicity Patients Phagocytes Phase Population Positioning Attribute Property Proteins Rag1 Mouse Reporting Research Rheumatism Role Serum Site Spleen Splenic Red Pulp Structure Symptoms Testing Vaccines Viral Viral Pathogenesis Viremia Virion Virus Virus Diseases adaptive immune response base cell type chikungunya infection chronic infection glycosylation human model human pathogen improved insight macrophage mouse model mutant nonhuman primate particle prevent response therapeutic development tool virus host interaction

项目摘要

PROJECT SUMMARY Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes epidemics of severe rheumatologic disease. The impact of CHIKV disease extends globally, with recent outbreaks occurring in Asia, Europe and the Americas. Up to 50% of patients report persistent rheumatologic symptoms, with incapacitating arthralgia lasting for months to years after infection. Chronic disease has been linked in humans and animal models with persistent CHIKV infection. Despite this, the host-viral interactions that dictate viral clearance or persistence are poorly defined. To identify adaptive mutations associated with chronic CHIKV infection, the Morrison laboratory isolated CHIKV from the circulation of a chronically-infected Rag1-/- mouse. This virus contained a mutation in the E2 glycoprotein (E2 K200R) that dramatically enhances viremia and viral dissemination in WT mice, leading to more severe disease outcomes. Moreover, introduction of an E2 K200R mutation into additional CHIKV strains or a closely related alphavirus, o'nyong nyong virus, also enhances viremia, demonstrating this mutation evades a host response that is operative against multiple alphaviruses. High viremia in humans and non-human primates infected with CHIKV has been associated with more severe acute disease and an increased potential for chronic disease. Therefore, this mutant virus provides a valuable tool to identify host and viral determinants of alphavirus dissemination and pathogenicity. The enhanced dissemination mediated by CHIKV E2 K200R (CHIKVE2 K200R) is independent of type I IFN, demonstrating that additional innate immune responses significantly contribute to CHIKV control. My preliminary data demonstrates that WT CHIKV particles are rapidly cleared from the circulation following intravenous inoculation, while CHIKVE2 K200R particles remain stably detectable. Depletion of phagocytic cells prevents clearance of WT CHIKV from the circulation, but has no impact on the circulating levels of CHIKVE2 K200R. These findings reveal a critical role for phagocytic cells in controlling WT CHIKV dissemination and suggest that CHIKVE2 K200R evades clearance by phagocytic cells. My objective is to define the phagocytic cells that are responsible for CHIKV clearance, and to define the viral determinants of clearance and escape. Based on my preliminary data, I hypothesize that splenic red pulp macrophages efficiently capture WT CHIKV, and that CHIKVE2 K200R evades this response by abrogating interactions with a conserved residue in the E1 glycoprotein, resulting in structural alterations that facilitate evasion of phagocytic cells. In Aim 1, I will precisely define the population of phagocytic cells that mediate CHIKV clearance from the circulation. In Aim 2, I will define viral determinants that mediate CHIKV clearance by phagocytic cells or escape of this clearance mechanism. The proposed research will significantly advance the field by defining new mechanisms of host control of alphavirus dissemination, and viral determinants of escape.

项目总结