Trafficking of Lymphocyte Subsets in Host Defense and Immunopathogenesis in COVID-19

COVID-19 宿主防御和免疫发病机制中淋巴细胞亚群的贩运

基本信息

批准号：
10927963
负责人：
JOSHUA M FARBER
金额：
$ 3.1万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927963
关键词：
2019-nCoV Antibodies Blood COVID-19 Cells Complex Data Dendritic Cells Disease Experimental Models FDA approved Flow Cytometry Genes Genetic Polymorphism Goals Hospitalization Host Defense Human Immune response Immune system Individual Infection Inflammation Interferons K-18 conjugate Leukocyte Trafficking Leukocytes Ligands Lung Lymphocyte Lymphocyte Subset Mediating Modeling Mononuclear Morbidity - disease rate Mus Natural Killer Cells Pathogenesis Pathology Patients Pattern Pneumonia Production Proteins Role SARS-CoV-2 infection Sampling System T-Lymphocyte Time Tissues Viral cell motility chemokine chemokine receptor cytokine experimental study genome wide association study human data influenza infection interest lymphocyte trafficking migration monocyte mouse model organ injury prevent receptor receptor expression small molecule therapeutic target trafficking

项目摘要

Selective expansion in the blood of lymphocyte subsets as defined by chemokine receptor expression can be used to infer activities for these cells in defense and/or pathology, while selective depletion of subsets from blood in pneumonia and other disorders can be used to infer the migration of these cells and roles for their receptors in trafficking into tissue. In FY 2023 we have continued to analyze chemokine receptor expression on T, NK, and dendritic cells and monocytes in the blood of individuals hospitalized due to COVID-19 as compared to healthy donors using multi-parameter flow cytometry. We have identified decreased expression of several chemokine receptors on the T and/or NK cells in patients hospitalized with COVID-19. We have considered whether depletion of cells expressing a given chemokine receptor might be due to the activity of a co-expressed receptor, and we have examined changes in the expression of receptors on T cells expressing pairs of receptors to identify receptors that may be acting as drivers versus those that are passengers. We have conducted experiments in K18-hACE2 mice infected with SARS-CoV-2 to pursue the findings from the patient samples and to understand more generally the roles for the chemokine system in host defense and immunopathogenesis in an experimental model of infection. In these studies, we have found that one of the driver receptors in humans is critical for the trafficking of plasmacytoid dendritic cells into the lungs of infected mice. Human data have suggested that these cells, which produce large amounts of type 1 and type 3 interferons, are critical in host defense in COVID-19. At the same time, we have been using a mouse model of influenza infection to compare the roles of the chemokine system in this model with the findings following infection with SARS-CoV-2.

趋化因子受体表达所定义的淋巴细胞亚群血液中的选择性扩张可用于推断这些细胞在防御和/或病理学中的活性，而肺炎和其他疾病中血液中的选择性耗竭可用于推断这些细胞的迁移以及其受体在运输中的迁移。在2023财年，我们继续分析与使用多参数流式细胞仪的健康供体相比，与健康的供体相比，与健康供体相比，在COVID-19上住院的个体血液中T，NK和树突细胞和单核细胞的趋化因子受体表达。我们已经确定在COVID-19的患者中，在T和/或NK细胞上的几个趋化因子受体的表达降低。我们已经考虑了表达给定趋化因子受体的细胞的耗竭可能是由于共表达受体的活性，并且我们检查了表达受体成对的受体表达的变化，以鉴定可能是驱动因素的受体，这些受体可能是驱动因素，而驱动器与乘客的受体相比。我们已经在感染SARS-COV-2的K18-HACE2小鼠中进行了实验，以追求患者样品的发现，并在一种实验性的感染模型中更普遍地了解趋化因子系统在宿主防御和免疫发病中的作用。在这些研究中，我们发现人类中的一个驱动器受体对于将血浆细胞类树突状细胞运输到感染小鼠的肺中至关重要。人类数据表明，这些细胞产生大量1型和3型干扰素，对于COVID-19的宿主防御至关重要。同时，我们一直在使用流感感染的小鼠模型来比较趋化因子系统在该模型中的作用与SARS-COV-2感染后的发现。