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：
10622542
负责人：
Ivona Vasile Pandrea
金额：
$ 39.75万
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/10622542
关键词：
2019-nCoV Acceleration Acquired Immunodeficiency Syndrome Address Aging Agreement Animals 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 Circulation Clinical Coculture Techniques Coronavirus Infections Data Disease Progression Elderly Emergency Situation Epithelial Cells Epithelium Failure Functional disorder Goals HIV HIV/AIDS 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 Organ 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 Seasons Site System Testing Therapeutic Viral Pathogenesis Virus Virus Diseases aged antiretroviral therapy cell injury co-infection comorbidity cytokine design experience extracellular gastrointestinal epithelium gastrointestinal symptom global health gut health gut microbiota high risk population immune activation inhibitor innovation insight microbial products mucosal site neutrophil nonhuman primate older patient pathogen prevent restoration severe COVID-19 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 感染患者和近 150 万 COVID-19 相关患者迄今为止（11 月 25 日）死亡人数已记录，新冠肺炎大流行是最严重的全球健康问题之一人类所知道的，也是美国的重大紧急情况。 COVID-19 对老年人或老年人的影响尤为严重有既往病史的受试者。考虑到大多数艾滋病毒感染者和艾滋病患者 (PLWHA) 在美国，感染者的年龄超过 50 岁，即使是较年轻的感染者也呈现出加速衰老和多重症状。与 HIV 引起的过度慢性炎症相关的合并症，预计 COVID-19 将在这个风险群体中尤其严重。与 HIV 类似，SARS-CoV-2 在肠道中复制，并且患者据报道，胃肠道症状会产生更严重的后果。具体机制是通过 SARS-CoV-2 对肠道健康的影响仍然难以捉摸，但这两种病毒很可能会增强肠道健康通过加剧肠道病变而相互影响。在这里，我们将检验以下假设： SARS-CoV-2重复感染后，SIV感染的PTMs的肠道功能障碍是通过触发发生的中性粒细胞在粘膜部位和随后的肠道的过度动员、激活和NETosis 附带损害。这种情况不仅会导致感染者感染更多病毒的风险增加严重形式的 COVID-19，而且还会通过 (i) 失去对 HIV 的控制而显着增强 HIV 的致病性在粘膜部位； (ii) 粘膜和全身免疫效应物的耗竭； (iii) 粘膜和全身的增加炎症程度； (iv) 先前存在的 SIV 相关合并症的加重。这个创新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 COVID-19 与触发或加剧 HIV 相关肠道功能障碍和合并症有关。我们将确定可能促使高危人群（例如艾滋病病毒感染者）改变治疗的风险因素。我们的高度该转化项目解决了 NIDDK 确定的关键科学问题，因此受到高度重视响应 RFA 20-021。