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Mechanistic Studies of Gut Dysfunction Exacerbation due to SARS-CoV-2 in HIV/SIV infected Individuals

HIV/SIV 感染者中 SARS-CoV-2 导致肠道功能恶化的机制研究

基本信息

批准号：
10452676
负责人：
Ivona Vasile Pandrea
金额：
$ 39.7万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2021-07-17 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452676
关键词：
2019-nCoV AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Aging Agreement Animals Blood Circulation CD4 Positive T Lymphocytes COVID-19 COVID-19 impact COVID-19 mortality COVID-19 pandemic COVID-19 pathogenesis COVID-19 patient Cells Cessation of life Chronic Clinical Coculture Techniques Coronavirus Infections Data Disease Progression Elderly Emergency Situation Epithelial Epithelial Cells Failure Functional disorder Goals Gut Mucosa HIV Immune Immunologics Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intestines Lead Lesion Macaca Macaca nemestrina Modeling Mononuclear Morbidity - disease rate Mucositis Mucous Membrane National Institute of Diabetes and Digestive and Kidney Diseases Natural History Neutrophil Activation Neutrophil Infiltration Outcome Pathogenicity Pathologic Pathway interactions Patients Persons Phagocytes Production Reporting Respiratory Tract Infections Risk Risk Factors SARS-CoV-2 exposure SARS-CoV-2 infection SIV Site Testing Therapeutic Viral Pathogenesis Virus Virus Diseases aged antiretroviral therapy body system cell injury co-infection comorbidity cytokine design experience extracellular gastrointestinal epithelium gastrointestinal symptom global health gut health gut microbiota high risk high risk population immune activation inhibitor innovation insight microbial mucosal site neutrophil nonhuman primate older patient pathogen prevent restoration severe COVID-19 simian human immunodeficiency virus superinfection systemic inflammatory response

项目摘要

Abstract With more than 60 million SARS-CoV-2 -infected patients worldwide and nearly 1.5 million COVID-19-related deaths recoreded thus far (November 25), the COVID pandemic is one of the most critical global health problem ever known to humankind, and a major emergency in the US. COVID-19 disproportionately impacts elders or subjects with pre-existing conditions. Considering that the majority of persons living with HIV and AIDS (PLWHA) in the US are aged over 50 years and that even the younger PLWHA present with accelerated aging and multiple comorbidities related to HIV-induced excessive chronic inflammation, it is expected that COVID-19 will be particularly severe in this risk group. Similar to HIV, SARS-CoV-2 replicates in the gut, and patients with gastrointestinal symptoms were reported to have a more severe outcome. The exact mechanism through which SARS-CoV-2 impacts the gut health remains elusive, however it is very likely that the two viruses can potentiate each other through exacerbation of the gut lesions. Here, we will test the hypothesis that exacerbation of the gut dysfunction of the SIV-infected PTMs after SARS-CoV-2 superinfection occurs through triggering excessive mobilization, activation and NETosis of neutrophils at mucosal site and consequent gut collateral damages. Such a scenario will result not only in an increased risk of the PLWHA to develop more severe forms of COVID-19, but also to a significant boost of HIV pathogenicity through (i) losing control of HIV at mucosal sites; (ii) depletion of mucosal and systemic immune effectors; (iii) increases of mucosal and systemic levels of inflammation; and (iv) enhancement of pre-existent SIV-related comorbidities. This innovative project is designed to assess pathogenic pathways impacted by SARS-CoV-2 in the gut, to understand the natural history of COVID-19 related to either triggering or exacerbating HIV-associated gut dysfunction and comorbidities. We will identify risk factors that could prompt therapy changes in high-risk individuals, such as the PLWH. Our highly translational project addresses key scientific questions identified as critical by the NIDDK, thus being highly responsive to RFA 20-021.

摘要