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

摘要 全球有6000多万SARS-CoV-2感染患者和近150万与新冠肺炎相关的患者 到目前为止(11月25日)死亡人数有所记录，COVID大流行是最严重的全球卫生问题之一 这是人类所知的，也是美国的重大紧急事件。新冠肺炎对老年人或老年人的影响不成比例 有既往病史的受试者。考虑到大多数艾滋病毒/艾滋病携带者(PLWHA) 在美国，年龄超过50岁的人，即使是年轻的PLWHA也出现了加速老龄化和多发性 与艾滋病毒诱导的过度慢性炎症有关的共病，预计新冠肺炎将 在这一风险群体中尤为严重。与艾滋病毒类似，SARS-CoV-2病毒在肠道内复制，患有 据报道，胃肠道症状的后果更严重。它的确切机制是 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 通过肠道损伤的恶化相互作用。在这里，我们将检验这一假设，即 SARS-CoV-2重叠感染后SIV感染的PTM患者肠道功能障碍的发生 中性粒细胞在粘膜部位和随后的肠道过度动员、激活和网状聚集 附带损害赔偿。这种情况不仅将导致PLWHA开发更多 严重形式的新冠肺炎，但也通过以下方式显著增强艾滋病毒的致病性：(一)失去对艾滋病毒的控制 在粘膜部位；(2)粘膜和全身免疫效应器的耗尽；(3)粘膜和全身的增加 炎症水平；以及(Iv)先前存在的SIV相关并存疾病的增加。这个创新的项目是 旨在评估肠道中受SARS-CoV-2影响的致病途径，以了解自然历史 新冠肺炎的发病与引发或加重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人改变治疗的风险因素，如PLWH。我们的高度重视 翻译项目解决了被NIDDK确定为关键的关键科学问题，因此非常 回应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.