Intersection of HIV-1 Tat and SARS-CoV-2 S1 on neuroinflammation

HIV-1 Tat 和 SARS-CoV-2 S1 对神经炎症的交叉作用

• 批准号: 10755919
• 负责人: Xuesong Chen
• 金额: $ 197.13万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 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 2026-08-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755919
• 关键词: 2019-nCoV; Affect; Arginine; Astrocytes; Attenuated; Award; Body Fluids; Brain; COVID-19; COVID-19 complications; COVID-19 mortality; Cells; Cellular biology; Complication; Development; Disease; Environment; Functional disorder; General Population; HIV; HIV-1; Immune response; Impairment; Lead; Lysosomes; Mediating; Mental Health; Neuroimmune; Neurologic; Neurologic Symptoms; Neuronal Injury; Outcome; Persons; Proteins; Proton Pump; Public Health; Research; Risk; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Testing; Transactivation; Vascular Diseases; Viral; Virus; adverse outcome; blood-brain barrier crossing; insight; knock-down; neuroinflammation; novel; novel therapeutic intervention; receptor mediated endocytosis; response; sensor; vacuolar H+-ATPase; viral RNA

Project Abstract COVID-19, caused by the infection of SARS-CoV-2, is associated with significant long-term neurological complications. Even mild COVID-19 can lead to such lasting neurological symptoms. Because only low or undetectable levels of SARS-CoV-2 viral RNA are detected in the brain, neurological complications of COVID- 19 may not result from direct SARS-CoV-2 infection in the brain; Rather, released SARS-CoV-2 viral factors- and/or virus-induced vascular dysfunction and aberrant neuroimmune responses may drive the development of neurological complications. COVID-19 outcomes are further complicated by HIV-1; Advanced HIV disease leads to delayed clearance of SARS-CoV-2, and people living with HIV-1 (PLWH) have an increased risk for adverse outcomes and mortality of COVID-19. However, it is not known how HIV-1 and SARS-CoV-2 may interact to affect the development of neurological complications. Our cell biology studies are aimed to determine early and upstream mechanisms governing interactions between HIV-1 and SARS-CoV-2 that could provide novel insights into the development of COVID-19-associated neurological complications in the general population and PLWH. The objective here is to determine the extent to which and mechanisms by which SARS-CoV-2 S1 and HIV-1 Tat intersect at endolysosomes to affect viral clearance and neuroinflammation. Based on our own findings, we will test the hypothesis that SLC38A9 functions as a sensor on endolysosome that mediates SARS-CoV-2 S1- and HIV-1 Tat-induced endolysosome de-acidification and dysfunction, impaired viral clearance, and neuroinflammation. Our hypothesis will be tested with three Specific Aims. (1) Determine the extent to which and mechanisms by which SARS-CoV-2 S1 and HIV-1 Tat induce endolysosome de-acidification and dysfunction. (2) Determine the extent to which endolysosome de- acidification induced by HIV-1 Tat affects SARS-CoV-2 clearance and the extent to which endolysosome de- acidification induced by SARS-CoV-2 S1 affects Tat-mediated HIV-1 LTR transactivation. (3) Determine the extent to which and mechanisms by which SARS-CoV-2 S1 and HIV-1 Tat affect astrocyte-dependent immune responses and neuronal injury. We expect to identify SLC38A9 as a sensor protein that mediates SARS-CoV-2 S1- and HIV-1 Tat-induced endolysosome de-acidification and dysfunction. Such an effect not only impairs the complete degradation of internalized SARS-CoV-2 but also lead to neuroinflammation and neuronal injury. The proposed mechanistic studies will not only lead to novel insights into the development of COVID-19-associated neurological complications in the general population and PLWH but also provide a rationale for developing novel therapeutic strategies such as blocking SLC38A9 and acidifying endolysosomes. Thus, the proposed research is responsive for this Urgent Award: COVID-19 Mental Health Research (PAR-22-113).

项目摘要