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

摘要 全球有超过6000万SARS-CoV-2感染患者，近150万COVID-19相关 截至目前（11月25日），COVID大流行是全球最严重的健康问题之一 人类所知的最严重的灾难，美国的重大紧急事件。COVID-19对老年人的影响不成比例， 受试者有预先存在的条件。考虑到大多数艾滋病毒感染者和艾滋病患者 在美国，年龄超过50岁，即使是年轻的PLWHA也会出现加速老化和多重 与艾滋病毒诱导的过度慢性炎症相关的合并症，预计COVID-19将是 在这个风险群体中尤为严重。与HIV类似，SARS-CoV-2在肠道中复制， 据报告，胃肠道症状的结局更严重。正是通过这种机制 SARS-CoV-2对肠道健康的影响仍然是难以捉摸的，但这两种病毒很可能可以增强 通过肠道病变的恶化而相互作用。在这里，我们将测试的假设，加剧 SIV感染的PTMs在SARS-CoV-2重叠感染后通过触发 中性粒细胞在粘膜部位和随后的肠道过度动员、活化和NETosis 附带损害这种情况不仅会增加艾滋病毒/艾滋病感染者的风险， 严重形式的COVID-19，但也通过（i）失去对艾滋病毒的控制， 在粘膜部位;（ii）粘膜和全身免疫效应物的耗竭;（iii）粘膜和全身免疫效应物的增加 炎症水平;和（iv）增强预先存在的SIV相关的合并症。这一创新项目是 旨在评估肠道中受SARS-CoV-2影响的致病途径， COVID-19与触发或加剧艾滋病毒相关的肠道功能障碍和合并症有关。我们 将确定可能促使高危个体（如PLWH）改变治疗的风险因素。我们高度 翻译项目解决了NIDDK确定为关键的关键科学问题，因此高度重视 响应RFA 20-021。

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.