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.

抽象的全球有超过6000万SARS-COV-2感染的患者，与150万COVID相关的患者到目前为止（11月25日）的死亡人数是最关键的全球健康问题之一（11月25日）曾经是人类的众所周知，是美国的主要紧急情况。 COVID-19不成比例地影响长老或具有先前条件的受试者。考虑到大多数患有艾滋病毒和艾滋病的人（PLWHA）在美国，年龄超过50岁，即使是年轻的PLWHA都有加速的衰老和多个与HIV引起的过度慢性炎症有关的合并症，预计Covid-19将是在这个风险组中特别严重。与HIV相似，SARS-COV-2在肠道中复制，患者据报道，胃肠道症状的结果更严重。确切的机制 SARS-COV-2影响肠道健康仍然难以捉摸，但是这两种病毒很可能会增强通过加剧肠道病变，彼此之间彼此。在这里，我们将检验以下假设 SARS-COV-2超级感染后，SIV感染的PTM的肠道功能障碍通过触发发生粘膜部位的中性粒细胞的过度动员，激活和肠病，随之而来的肠道抵押损失。这种情况不仅会导致PLWHA发展更多的风险严重的Covid-19形式，但也通过（i）失去对HIV的控制，从而显着提高HIV致病性在粘膜部位；（ii）粘膜和全身免疫效应子的耗竭；（iii）粘膜和全身性的增加炎症水平；（iv）增强与SIV相关的合并症的增强。这个创新的项目是旨在评估肠道中SARS-COV-2影响的致病途径，以了解自然史与触发或加剧与HIV相关的肠道功能障碍和合并症有关的COVID-19。我们将确定可能促使高风险个体（例如PLWH）发生治疗变化的危险因素。我们的高度翻译项目解决了NIDDK认为至关重要的关键科学问题，因此很高响应RFA 20-021。