The Role of Obesity on Alphavirus Disease Severity

项目摘要/摘要 基孔肯雅病毒(CHIKV)是一种NIAID B类病原体，可导致衰弱的关节炎 这种疾病可能会持续数年。2013年，美洲发生了大规模的CHIKV疫情， 估计有3990万人感染。密切相关的病毒包括罗斯河病毒(RRV)和 马亚罗病毒(MAYV)，每年在澳大利亚和南方造成数千例关节炎病例 分别是美国。虽然先前的研究表明，宿主免疫反应介导了 由这些病毒引起的疾病，对作为严重疾病危险因素的宿主辅助因素知之甚少 由这些病毒引起的。一个主要的辅因是肥胖，它影响着42.4%的美国人和每8个人中就有一个 -在感染几种病毒期间与疾病严重程度有关；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，肥胖的小鼠 感染CHIKV、RRV或MAYV的人会经历更严重的疾病后果。此外，我们 在我们的小鼠模型中，我发现了几种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)确定新的治疗靶点，以治疗严重的甲型病毒疾病和 (2)增进我们对与增加的 由几种病毒病原体引起的肥胖者的疾病严重程度有助于减少疾病和残疾。这个 这项建议旨在达到我们的长期目标，目的是(I)界定肥胖的作用- 瘦和肥胖宿主中甲型病毒致病的相关免疫基因和(Ii)确定相互作用 在甲型病毒感染背景下肥胖的巨噬细胞、NK细胞和中性粒细胞之间的关系。我们的中央 假说是肥胖诱导的促炎细胞因子促进了疾病严重性的增加 通过改变几个免疫细胞群的渗透和激活而感染甲型病毒。这些研究 理由有两个：(一)定义肥胖对甲型病毒疾病严重程度的影响；(二)利用肥胖 确定宿主候选基因以开发新的治疗方法。在目标1中，我们将使用基因敲除小鼠、耗竭和 细胞因子治疗以确定几种与体重密切相关的细胞因子的影响 感染的小鼠，我们希望这将导致更好地理解甲型病毒的发病机制并识别 治疗靶点。在目标2中，我们将使用流式细胞术和转录组学来定义肥胖对 甲型病毒感染过程中免疫细胞的渗透和激活，我们期待这将提供新的见解 变成瘦削和肥胖宿主发病的免疫介质，这可以成为治疗学的靶点。这个 拟议的研究试图洞察肥胖症和甲型病毒之间的基本关系 发病机制和确定新的治疗靶点以减少甲型病毒病。

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.