The Role of Obesity on Alphavirus Disease Severity

肥胖对甲病毒病严重程度的影响

• 批准号: 10303398
• 负责人: James D Weger
• 金额: $ 23.06万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303398
• 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; 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 cytokines; therapeutic target; transcriptome sequencing; transcriptomics; translational impact; vaccine access

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.

项目总结/摘要 基孔肯雅病毒（CHIKV），NIAID类别B病原体，引起使人衰弱的关节炎， 这种疾病可以持续数年。2013年，整个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澳大利亚造成数千例关节炎病例， 美国，分别。虽然以前的研究表明，宿主免疫反应介导了 尽管这些病毒引起的疾病，但对作为严重疾病风险因素的宿主辅因子知之甚少 由这些病毒引起的。一个主机辅因子-肥胖，影响42.4%的美国人和1/8的人 在世界范围内-与感染几种病毒期间的疾病严重程度有关;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， 感染CHIKV、RRV或MAYV的人经历更严重的疾病结果。而且我们 已经在我们的小鼠模型中鉴定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）确定治疗严重甲病毒病的新治疗靶点， (ii)增加我们对与增加的 疾病的严重性，肥胖的人所造成的几种病毒病原体，以减少疾病和残疾。的 这项建议旨在达致我们的长远目标，其目的是：（i）界定肥胖症的角色- 相关免疫基因对瘦型和肥胖型宿主中甲病毒发病机制的影响，以及（ii）定义相互作用 在甲病毒感染的背景下，巨噬细胞、NK细胞和嗜中性粒细胞与肥胖之间的关系。我们的中央 假设是肥胖诱导的促炎细胞因子促进疾病严重性的增加， 通过改变几种免疫细胞群体的浸润和活化，可以抑制甲病毒感染。这些研究“ 基本原理是双重的：（i）定义肥胖对甲病毒疾病严重程度的影响，以及（ii）利用肥胖来 鉴定宿主候选基因以开发新的治疗剂。在目标1中，我们将使用基因敲除小鼠，耗尽， 细胞因子治疗以确定与体重强烈相关的几种细胞因子在 感染的小鼠，我们预计这将导致更好地了解甲病毒的发病机制，并确定 治疗目标在目标2中，我们将使用流式细胞术和转录组学来确定肥胖对 甲病毒感染期间免疫细胞浸润和激活，我们期望这将提供新的见解 在瘦和肥胖的宿主中转化为发病机制的免疫介质，其可以被治疗剂靶向。的 拟议中的研究旨在深入了解肥胖和甲病毒之间的基本关系 致病机制和确定新的治疗靶点，以减少甲病毒疾病。