Hu Shuang, Buser Elise, Arredondo Juan, Relyea Dylan, Santos Rocha Clarissa, Dandekar Satya
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States.
Front Microbiol. 2022 Apr 14;13:879152. doi: 10.3389/fmicb.2022.879152. eCollection 2022.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of the COVID-19 pandemic, is initiated by its binding to the ACE2 receptor and other co-receptors on mucosal epithelial cells. Variable outcomes of the infection and disease severity can be influenced by pre-existing risk factors. Human immunodeficiency virus (HIV), the cause of AIDS, targets the gut mucosal immune system and impairs epithelial barriers and mucosal immunity. We sought to determine the impact and mechanisms of pre-existing HIV infection increasing mucosal vulnerability to SARS-CoV-2 infection and disease. We investigated changes in the expression of ACE2 and other SARS-CoV-2 receptors and related pathways in virally inflamed gut by using the SIV infected rhesus macaque model of HIV/AIDS. Immunohistochemical analysis showed sustained/enhanced ACE2 expression in the gut epithelium of SIV infected animals compared to uninfected controls. Gut mucosal transcriptomic analysis demonstrated enhanced expression of host factors that support SARS-CoV-2 entry, replication, and infection. Metabolomic analysis of gut luminal contents revealed the impact of SIV infection as demonstrated by impaired mitochondrial function and decreased immune response, which render the host more vulnerable to other pathogens. In summary, SIV infection resulted in sustained or increased ACE2 expression in an inflamed and immune-impaired gut mucosal microenvironment. Collectively, these mucosal changes increase the susceptibility to SARS-CoV-2 infection and disease severity and result in ineffective viral clearance. Our study highlights the use of the SIV model of AIDS to fill the knowledge gap of the enteric mechanisms of co-infections as risk factors for poor disease outcomes, generation of new viral variants and immune escape in COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染是导致新冠疫情的原因，它通过与黏膜上皮细胞上的血管紧张素转换酶2（ACE2）受体及其他共受体结合而引发感染。既往存在的危险因素会影响感染的不同结果和疾病严重程度。人类免疫缺陷病毒（HIV）是艾滋病的病原体，它靶向肠道黏膜免疫系统，损害上皮屏障和黏膜免疫。我们试图确定既往HIV感染增加黏膜对SARS-CoV-2感染和疾病易感性的影响及机制。我们利用感染了猴免疫缺陷病毒（SIV）的恒河猴艾滋病模型，研究了病毒感染引起炎症的肠道中ACE2和其他SARS-CoV-2受体的表达变化以及相关途径。免疫组化分析显示，与未感染的对照组相比，感染SIV的动物肠道上皮中ACE2表达持续/增强。肠道黏膜转录组分析表明，支持SARS-CoV-2进入、复制和感染的宿主因子表达增强。对肠道管腔内容物的代谢组分析揭示了SIV感染的影响，表现为线粒体功能受损和免疫反应降低，这使宿主更容易受到其他病原体的侵害。总之，SIV感染导致炎症和免疫受损的肠道黏膜微环境中ACE2表达持续或增加。这些黏膜变化共同增加了对SARS-CoV-2感染的易感性和疾病严重程度，并导致病毒清除无效。我们的研究强调了利用艾滋病的SIV模型来填补共感染肠道机制方面的知识空白，这些机制是导致新冠疫情中疾病预后不良、新病毒变种产生和免疫逃逸的危险因素。
