The Role of Obesity on Alphavirus Disease Severity

肥胖对甲病毒病严重程度的影响

基本信息

批准号：
10437924
负责人：
James D Weger
金额：
$ 19.03万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437924
关键词：
2019-nCoV Adult Affect Alphavirus Alphavirus Infections American Americas Antibodies Antiviral Agents Arthritis Australia Biological Response Modifiers Body Weight decreased CCL2 gene CCL4 gene CCR5 gene CSF3 gene Candidate Disease Gene Category B pathogen Cells Chikungunya virus Chronic Data Dengue Virus Disease Disease Outbreaks Disease Outcome Enzyme-Linked Immunosorbent Assay Epidemiology Flow Cytometry Future Gene Expression Genes Goals Human Immune Immune response Immunologics Infection Infiltration Inflammation Inflammatory Influenza A virus Interferon Type II Knockout Mice Knowledge Leukocytes Macrophage Activation Mayaro virus Measures Mediating Mus National Institute of Allergy and Infectious Disease Natural Killer Cells Neutrophil Activation Neutrophil Infiltration Obese Mice Obesity Pathogenesis Pathogenicity Pathology Persons Population Public Health Quantitative Reverse Transcriptase PCR Recombinant Cytokines Research Research Personnel Risk Factors Role Ross river virus Severity of illness South America Swelling Testing Therapeutic Thinness Tissues Togaviridae Transgenic Mice Viral Pathogenesis Virus Virus Diseases Virus Replication Work cell type chemokine chikungunya chikungunya infection cofactor cytokine design disability experience experimental study high risk human disease immune activation influenzavirus innovation insight macrophage mouse model neutrophil new therapeutic target novel novel therapeutics obese person pathogen pathogenic virus prevent response targeted treatment therapeutic target transcriptome sequencing transcriptomics translational impact vaccine access

项目摘要

Project Summary/Abstract Chikungunya virus (CHIKV), an NIAID category B pathogen, causes a debilitating arthritic disease that can last for years. A massive outbreak of CHIKV occurred throughout the Americas in 2013, with an estimated 39.9 million people infected. Closely related viruses include Ross River virus (RRV) and Mayaro virus (MAYV), which produce thousands of annual cases of arthritic disease in Australia and South America, respectively. While previous research demonstrates that the host immune response mediates the disease caused by these viruses, little is known about the host cofactors that act as risk factors for severe disease caused by these viruses. One host cofactor—obesity, which affects 42.4% of Americans and 1 in 8 people worldwide—has been associated with disease severity during infection with several viruses; including, Influenza virus, SARS-CoV-2, and dengue virus. Similarly, our recent experimental data suggest that obese mice infected with either CHIKV, RRV, or MAYV experience more severe disease outcomes. Furthermore, we have identified several cytokines and chemokines that correlate strongly with obesity in our mouse model during infection. Our long-term goals are: (i) to identify novel therapeutic targets to treat severe alphavirus disease and (ii) to increase our fundamental knowledge regarding the underlying mechanisms associated with the increased disease severity in obese people caused by several viral pathogens towards reducing illness and disability. The objectives of this proposal, directed towards attaining our long-term goal, are to (i) define the role of obesity- associated immune genes on alphavirus pathogenesis in lean and obese hosts and (ii) define the interplay between macrophages, NK cells, and neutrophils with obesity in the context of alphavirus infection. Our central hypothesis is that pro-inflammatory cytokines induced by obesity promote an increase in disease severity upon alphavirus infection by altering infiltration and activation of several immune cell populations. These studies' rationale is two-fold: (i) to define obesity's impact on alphavirus disease severity and (ii) to use obesity to identify host gene candidates to develop novel therapeutics. In Aim 1, we will use knockout mice, depletion, and cytokine treatment to determine the impact of several cytokines that strongly correlate with bodyweight in infected mice, which we expect will lead to a better understanding of alphavirus pathogenesis and identify therapeutic targets. In Aim 2, we will use flow cytometry and transcriptomics to define the impact of obesity on immune cell infiltration and activation during alphavirus infection, which we expect will provide novel insight into immune mediators of pathogenesis in lean and obese hosts, which can be targeted by therapeutics. The proposed studies seek to provide insight into the fundamental relationship between obesity and alphavirus pathogenesis and identify novel therapeutic targets towards reducing alphavirus disease.

项目摘要/摘要 B类病原体Chikungunya病毒（CHIKV）导致令人衰弱的Artritic 可以持续多年的疾病。 2013年，整个美洲发生了大规模的Chikv爆发，估计有3990万人感染。密切相关的病毒包括罗斯河病毒（RRV）和 Mayaro病毒（Mayv），该病毒在澳大利亚和南部产生数千例年度artritic疾病病例美国。虽然先前的研究表明，宿主免疫反应介导这些病毒引起的疾病，对充当严重疾病的危险因素的宿主辅助因子知之甚少由这些病毒引起。一个宿主辅助因子 - 肥胖，影响42.4％的美国人，其中1人中有1人在全球范围内，已经与多种病毒感染期间疾病严重程度有关；包括，流感病毒，SARS-COV-2和登革热病毒。同样，我们最近的实验数据表明肥胖小鼠感染了CHIKV，RRV或MAYV会经历更严重的疾病结果。此外，我们已经确定了几种细胞因子和趋化因子，它们在我们的小鼠模型中与肥胖密切相关的细胞因子和趋化因子。感染。我们的长期目标是：（i）确定治疗严重α病毒疾病和（ii）提高我们关于与增加相关的潜在机制的基本知识肥胖者的疾病严重程度是由几种病毒病原体引起的，用于减少疾病和残疾。这该提议的目标是针对实现我们的长期目标的，是（i）定义肥胖的作用 - 瘦和肥胖宿主的α病毒发病机理上的相关免疫原，（ii）定义相互作用巨噬细胞，NK细胞和中性粒细胞在α病毒感染的背景下具有肥胖症。我们的中心假设是肥胖引起的促炎性细胞因子会促进疾病严重程度的增加 α病毒感染通过改变了几个免疫细胞种群的浸润和激活。这些研究' 理由是两个方面：（i）定义肥胖对α病毒疾病严重程度的影响，以及（ii）使用肥胖症鉴定宿主基因候选者开发新疗法。在AIM 1中，我们将使用淘汰小鼠，部署和细胞因子治疗以确定几种与体重密切相关的几种细胞因子的影响感染的小鼠，我们期望这将使人们对α病毒发病机理有更好的了解并识别治疗靶标。在AIM 2中，我们将使用流式细胞术和转录组学来定义肥胖对 α病毒感染期间的免疫细胞浸润和激活，我们期望这将提供新的见解进入瘦肉和肥胖宿主的发病机理的免疫介质，可以通过治疗来靶向。拟议的研究试图洞悉肥胖与α病毒之间的基本关系发病机理并确定了降低α病毒疾病的新型治疗靶标。