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Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV)

基孔肯雅病毒（CHIKV）与年龄相关的易感性机制

基本信息

批准号：
10436970
负责人：
JANKO Z. NIKOLICH
金额：
$ 33.77万
依托单位：
UNIVERSITY OF ARIZONA
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：
2018-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436970
关键词：
Ablation Acute Adult African Aging Alphavirus Antibodies Antibody Formation Arthralgia Arthritis Asian B-Lymphocytes Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caribbean region Cells Cessation of life Chikungunya virus Chronic Clinical Color Country Defect Disease Elderly Environment Environmental Risk Factor Epidemic Exanthema Exhibits Exposure to Fever Florida Genetic Human Immune Immune System Diseases Immune response Immunity Impairment In Situ Hybridization Individual Infection Inflammation Inflammatory Interferon-alpha Interleukin-17 Joints Kidney Knockout Mice Lead Liver Measures Mediating Modeling Morbidity - disease rate Mus Organ Organism Outcome Pathogenesis Pathogenicity Pathology Population Predisposition Production Regulation Reporter Reporting Risk Risk Factors Role Serum Severity of illness Signal Transduction Surface T cell response T-Lymphocyte Testing Transforming Growth Factor beta Viral Viral Pathogenesis Virus Virus Diseases Wild Type Mouse adaptive immune response age related chikungunya infection cytokine experimental study immunological intervention immunopathology improved insight joint inflammation macrophage mature animal mortality mosquito-borne mouse model neutralizing antibody prevent response tool transmission process vector mosquito viral resistance young adult

项目摘要

Abstract Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV disease (CHIKVD), which includes fever, rash, joint pain and sometimes involvement of parenchymal organs (liver, brain, kidney). Moreover, CHIKVD tends to persist in many, particularly older, subjects in the form of highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related vulnerability to CHIKV. We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV- infected elderly humans, and used it to begin to elucidate mechanisms underlying the age-related dysfunction of the immune response to CHIKV infection. We found an increase in TGFβ, concomitant with qualitative and quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGFβ antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology and improve production of neutralizing antibodies. TGFβ was also elevated and neutralizing Ab reduced in older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we propose to dissect mechanisms that lead to dysregulated TGFβ production and to elucidate how TGFβ contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in old CHIKV-infected mice, increased TGFβ dysregulates type 1 (T1) immunity against CHIKV by acting upon soluble factors, Th1, B and perhaps Th17, cells. This hypothesis and related questions and sub- hypotheses will be tested in the following Aims: SA1. To test the roles of T and B cell-intrinsic and extrinsic (environmental) factors in suboptimal adaptive responses of old mice to CHIKV. SA2. To examine whether and how elevated TGFβ acts directly on old adaptive immune cells. These experiments will provide detailed insights into pathogenesis and immunity against CHIKV and pave the way for immune interventions against CHIKVD/chronic arthritis in older adults.

摘要