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 由SARS-CoV-2感染引起的新冠肺炎与重大的长期神经系统疾病有关 并发症。即使是温和的新冠肺炎也会导致这种持久的神经症状。因为只有低或 在大脑中检测到无法检测到的SARS-CoV-2病毒RNA水平，COVID的神经并发症- 19可能不是脑部直接感染SARS-CoV-2；相反，释放的SARS-CoV-2病毒因子- 和/或病毒诱导的血管功能障碍和异常的神经免疫反应可能推动 神经系统并发症。新冠肺炎的结局因艾滋病毒-1而进一步复杂化；晚期艾滋病毒疾病 导致SARS-CoV-2清除延迟，艾滋病毒携带者(PLWH)患上SARS-CoV-2的风险增加 新冠肺炎的不良反应和死亡率。然而，目前尚不清楚HIV-1和SARS-CoV-2如何 相互作用，影响神经系统并发症的发展。我们的细胞生物学研究旨在 确定控制HIV-1和SARS-CoV-2之间相互作用的早期和上游机制 为新冠肺炎相关神经系统并发症的一般发展提供新的见解 人口和PLWH。这里的目标是确定在什么程度上和通过什么机制 SARS-CoV-2S1和HIV-1Tat在内溶酶体内相交，影响病毒清除和神经炎症。 基于我们自己的发现，我们将检验SLC38A9作为内溶酶体传感器的假设 介导SARS-CoV-2 S1-和HIV-1 Tat诱导的内溶酶体脱酸和功能障碍， 病毒清除受损，神经发炎。我们的假设将通过三个具体目标进行检验。(1) 确定SARS-CoV-2 S1和HIV-1 TAT诱导的程度和机制 内溶酶体脱酸和功能障碍。(2)确定内溶酶体降解的程度 HIV-1Tat诱导的酸化影响SARS-CoV-2的清除和内溶酶体降解的程度 SARS-CoV-2S1诱导的酸化影响TAT介导的HIV-1LTR反式激活。(3)确定 SARS-CoV-2S1和HIV-1Tat对星形胶质细胞依赖免疫的影响程度及机制 反应和神经元损伤。我们希望将SLC38A9确定为介导SARS-CoV-2病毒的传感器蛋白 S1-和HIV-1 TAT诱导的内溶酶体脱酸和功能障碍。这样的影响不仅损害了 SARS-CoV-2内化后完全降解，但也会导致神经炎症和神经元损伤。这个 拟议的机制研究不仅将为新冠肺炎相关的发展带来新的见解 一般人群和PLWH的神经系统并发症，但也提供了一个发生 新的治疗策略，如阻断SLC38A9和酸化内溶酶体。因此，拟议的 研究响应这个紧急奖项：新冠肺炎精神健康研究(PAR-22-113)。