Mechanisms of SARS-CoV-2 pathogenesis during HIV/SIV infection

HIV/SIV 感染期间 SARS-CoV-2 的发病机制

• 批准号: 10685195
• 负责人: Megan A O'Connor
• 金额: $ 81.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-28 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685195
• 关键词: 16S ribosomal RNA sequencing; 2019-nCoV; ACE2; Acceleration; Acute; Affect; Alveolar Macrophages; Animals; Automobile Driving; B-Lymphocytes; COVID-19; COVID-19 prevention; COVID-19 severity; COVID-19 vaccination; Cells; Cessation of life; Disease; Disease Outcome; Disease Progression; Enteral; Enterocytes; Epithelial Cells; Evolution; Frequencies; Functional disorder; Gastrointestinal tract structure; Generations; HIV; HIV Infections; HIV/AIDS; Homeostasis; Hospitalization; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunity; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunosuppression; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Intestines; Link; Lung; Macaca nemestrina; Macrophage; Measures; Modeling; Mucous Membrane; Outcome; Pathogenesis; Pathologic; Persons; Phase; Play; Proteobacteria; Pulmonary Inflammation; Pulmonary Pathology; Rectum; Respiratory System; Risk; Risk Factors; Risk Reduction; Role; SARS-CoV-2 antiviral; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 variant; SIV; Severity of illness; T cell response; Testing; Viral; Viral Load result; Viral hepatitis; Virulent; Virus; Virus Diseases; Virus Shedding; Work; adaptive immunity; antiviral drug development; associated symptom; co-infection; comorbidity; dysbiosis; exhaustion; extracellular; gastrointestinal; high risk; immune activation; immunopathology; innovation; insight; lung microbiome; microbial; microbial community; microbiome; microbiome composition; monocyte; mortality; mucosal site; neutrophil; nonhuman primate; oral commensal; receptor; rectal; rectal microbiome; respiratory; respiratory pathogen; response; severe COVID-19; variants of concern; viral transmission

PROJECT SUMMARY/ABSTRACT COVID-19 vaccination reduces the risk of SARS-CoV-2 infection and severe disease, but almost half of hospitalized breakthrough cases are in immunocompromised individuals. HIV infection is an independent risk factor for severe COVID-19, hospitalization, and mortality. Immunocompromised individuals are more likely to have prolonged SARS-CoV-2 infection and viral shedding, increasing the risk of viral transmission and allowing for rapid evolution of more virulent strains. Therefore, investigating SARS-CoV-2 pathogenesis in the context of immunosuppression is urgently needed to reveal factors driving severe COVID-19. SARS-CoV-2 lung pathogenesis is characterized by infiltration of innate and adaptive immune cells into the lung and induction of an inflammatory immune response. Similar mechanisms of inflammation and immune dysfunction during HIV infection contribute to systemic HIV pathogenesis and lung pathology. Therefore, dysregulation of immune responses during HIV infection could induce severe disease outcomes during SARS-CoV-2 coinfection. SARS- CoV-2 replication occurs in both respiratory and gastrointestinal mucosal sites and enteric symptoms are associated with COVID-19. There is a defined link between gastrointestinal microbial dysbiosis with accelerated HIV disease progression and an emerging role of lung and intestinal microbial dysbiosis with severe COVID-19. Given that the microbiome plays an important role in maintaining mucosal function and homeostasis, shifts in microbial communities due to HIV infection could contribute to inflammation and immune activation that would drive exacerbated SARS-CoV-2 pathogenesis. Here, we will test the hypothesis that increased immune dysfunction and exhaustion, inflammation, and microbial dysbiosis during HIV infection promote enhanced SARS-CoV-2 lung pathogenesis. We will leverage the pigtail macaque simian immunodeficiency virus (SIV) model of rapid HIV/AIDS and will test this hypothesis during a state of inflammatory untreated SIV infection and during primary and secondary SARS-CoV-2 viral challenges. We will evaluate the roles of SIV-induced immunosuppression and altered alveolar macrophage and neutrophil function on SARS-CoV-2 pathogenesis and pulmonary pathology. We will determine whether HIV infection causes gastrointestinal tract and lung microbial dysbiosis and its association with SARS-CoV-2 disease severity. Lastly, we will determine whether increased immune exhaustion during HIV infection promotes deficits in the generation of primary anti-viral SARS- CoV-2 responses that impairs protection from heterologous SAR-CoV-2 re-challenge. These studies will contribute to our understanding of how normal immunity drives SARS-CoV-2 lung pathophysiology and will dissect how perturbations of immune responses during HIV infection contribute to enhanced disease.

项目摘要/摘要 接种新冠肺炎疫苗降低了感染SARS-CoV-2和严重疾病的风险，但几乎一半的人 住院的突破性病例发生在免疫功能低下的人身上。艾滋病毒感染是一种独立的风险 严重新冠肺炎、住院和死亡的因素。免疫功能低下的人更有可能 延长了SARS-CoV-2感染和病毒脱落的时间，增加了病毒传播的风险，并允许 用于更强毒力菌株的快速进化。因此，在SARS-CoV-2致病机制研究的背景下， 迫切需要免疫抑制来揭示导致严重新冠肺炎的因素。SARS-CoV-2肺 发病机制的特点是先天免疫细胞和获得性免疫细胞渗透到肺内，并诱导 一种炎症性免疫反应。HIV感染过程中炎症和免疫功能障碍的相似机制 感染导致了全身性HIV的发病和肺部病理。因此，免疫调节失调 在SARS-CoV-2合并感染期间，HIV感染期间的反应可能会导致严重的疾病结局。非典-- CoV-2复制发生在呼吸道和胃肠道粘膜部位，肠道症状为 与新冠肺炎相关。胃肠道微生物失调与加速的 艾滋病毒疾病进展和肺和肠道微生物失调的新作用与严重的新冠肺炎。 鉴于微生物组在维持粘膜功能和动态平衡方面发挥着重要作用， 艾滋病毒感染引起的微生物群落可能会促进炎症和免疫激活，从而 DRIVE加剧了SARS-CoV-2的致病过程。在这里，我们将检验一种假设，即增强免疫力 HIV感染期间的功能障碍和疲惫、炎症和微生物失调促进增强 SARS-CoV-2的肺发病机制。我们将利用尾巴猕猴免疫缺陷病毒(SIV) 快速艾滋病毒/艾滋病模型，并将在炎症性未经治疗的SIV感染状态和 在原发和继发SARS-CoV-2病毒挑战期间。我们将评估SIV诱导的作用 SARS-CoV-2免疫抑制及肺泡巨噬细胞和中性粒细胞功能改变 和肺部病理。我们将确定艾滋病毒感染是否会导致胃肠道和肺部 微生物失调及其与SARS-CoV-2疾病严重程度的关系。最后，我们将确定是否 HIV感染过程中免疫衰竭的增加促进了初级抗病毒SARS的产生缺陷。 CoV-2应答削弱了对异源SAR-CoV-2重新攻击的保护。这些研究将 有助于我们理解正常的免疫如何驱动SARS-CoV-2的肺部病理生理学和将 剖析艾滋病毒感染期间免疫反应的扰动如何导致疾病加重。