Investigating the role and therapeutic potential of the alpha5beta1 integrin in risk factors for COVID-19-associated cognitive impairment

研究 α5β1 整合素在 COVID-19 相关认知障碍危险因素中的作用和治疗潜力

• 批准号: 10658178
• 负责人: TIONE BURANDA
• 金额: $ 225.41万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658178
• 关键词: 2019-nCoV; ACE2; Acceleration; Acute; Address; Animals; Bilateral; Binding; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Ischemia; Brain Pathology; COVID-19; COVID-19 morbidity; COVID-19 risk; Carotid Stenosis; Cell Culture Techniques; Cell membrane; Cell surface; Cells; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Clinical; Clinical Research; Cognitive; Complex; Contracts; Cytoplasmic Tail; Data; Dementia; Elderly; Endothelial Cells; Exposure to; Female; Functional disorder; Gel; Hypoxia; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inbred BALB C Mice; Incidence; Individual; Infection; Integrin Inhibition; Integrin alpha5beta1; Integrins; Interphase Cell; Label; Link; Measurement; Modeling; Morbidity - disease rate; Mus; Neurocognitive; Outcome; Pathogenicity; Pathologic; Pathology; Patients; Play; Predisposition; Prevalence; Productivity; Proteins; RGD (sequence); Receptor Inhibition; Risk; Role; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 variant; Serum; Severities; Signal Transduction; Stroke; Surface; Talin; Therapeutic; Therapeutic Studies; Up-Regulation; Vascular Dementia; Viral; Virus; Virus Receptors; age related; aged; aging population; base; behavior test; blood-brain barrier disruption; chemokine; comorbidity; cytokine; effective therapy; functional outcomes; improved; in vivo; inhibitor; male; monolayer; mortality; neuroinflammation; non-demented; novel; post SARS-CoV-2 infection; post stroke; post-COVID-19; prevent; receptor; receptor mediated endocytosis; rho GTP-Binding Proteins; severe COVID-19; spatiotemporal; systemic inflammatory response; theories; white matter damage

ABSTRACT Rapidly emerging evidence has characterized the association between vascular dementia (VaD) and increased COVID-19 incidence, morbidity, and post-COVID cognitive decline. We theorize that brain vascular pathology in VaD and additional pathophysiologic features such as blood-brain barrier (BBB) disruption and reduced cerebral blood flow may directly contribute to both VaD and COVID-19. Several lines of evidence support this hypothesis. First, we have demonstrated that SARS-CoV-2 binds to the vascular integrin α5β1 receptor to infect cells, the same receptor we have also linked to BBB disruption in brain ischemia (stroke) models and chronic bilateral carotid artery stenosis (BCAS), which models pathophysiological aspects of VaD such as reduced cerebral blood flow, BBB disruption, neuroinflammation, white matter damage, and cognitive decline. Second, integrin α5β1 is substantially upregulated in an age-dependent fashion (aged>young) in the brain vasculature after stroke and BCAS, and inhibition of this receptor with the clinically-validated integrin α5β1 pentapeptide inhibitor ATN-161 lessens BBB disruption and cognitive impairment in these models. Third, SARS-CoV-2 infection also increases integrin α5β1 expression in vivo and disrupts the BBB. Forth, preliminary results suggest that SARS-CoV-2 infection after BCAS further increases morbidity vs. BCAS or infection alone and accelerates brain vascular integrin α5β1 upregulation. Fifth, ATN-161 inhibits SARS-CoV-2 infection in vitro and in vivo and prevents SARS- CoV-2-induced increased expression of α5β1 integrin. Finally, although angiotensin-converting enzyme 2 (ACE2) is the canonical receptor for viral entry (internalization and fusion) into host cells, its ectodomain binds the viral spike protein (S-protein) on the surface to facilitate virus attachment and access into host cells through receptor-mediated endocytosis using an RGD motif. As many cell-surface integrins also bind RGD, we and others have provided compelling evidence that integrins are co-receptors of the virus. Additionally, we have shown that talin-dependent integrin activation is required for SARS-CoV-2 infectivity. Consistent with our results, previous studies have shown that α5β1 and ACE2 engage in signaling crosstalk likely driven by mutual interaction at their cytoplasmic tails. Building on these findings, we hypothesize that (i) integrin α5β1 plays an important age-dependent pathogenic role in the association between SARS-CoV-2 infection and VaD by worsening pre-existing VaD after COVID-19, (ii) ATN-161 treatment before, during, or after COVID-19 infection will stabilize BBB integrity to improve COVID-19 neurocognitive outcomes in the context of pre-existing vascular dementia, and (iii) integrin α5β1 signaling regulates infectivity, and its upregulation potentiates dysregulation of the BBB. To investigate these hypotheses, we propose to 1). Demonstrate that experimental VaD worsens COVID-19 morbidity and subsequent cognitive decline, 2). Determine the therapeutic potential of integrin α5β1 inhibition in improving VaD post-COVID morbidity and cognitive decline, 3). Determine the signaling mechanism of integrin α5β1 required for SARS-CoV-2 productive infection and dysregulation of cell barrier function.

摘要 迅速出现的证据表明，血管性痴呆（VaD）与增加的 COVID-19发病率、发病率和COVID后认知能力下降。我们的理论是， VaD和其他病理生理学特征，如血脑屏障（BBB）破坏和脑功能减退 血流可能直接导致VaD和COVID-19。有几条证据支持这一假设。 首先，我们已经证明SARS-CoV-2与血管整合素α5β1受体结合感染细胞， 同样的受体，我们也联系到脑缺血（中风）模型和慢性双侧血脑屏障破坏 颈动脉狭窄（BCAS），其模拟VaD的病理生理学方面，例如脑血流量减少 血流、BBB破坏、神经炎症、白色物质损伤和认知能力下降。第二，整合素α5β1是 在中风后脑血管系统中以年龄依赖性方式（老年>年轻）显著上调， BCAS，以及使用经临床验证的整合素α5β1五肽抑制剂ATN-161抑制该受体 减轻了这些模型中的BBB破坏和认知障碍。第三，SARS-CoV-2感染也增加 整合素α5β1在体内表达并破坏BBB。第四，初步结果表明，SARS-CoV-2 与BCAS或单独感染相比，BCAS后感染进一步增加了发病率， 整合素α5β1上调。第五，ATN-161在体外和体内抑制SARS-CoV-2感染，预防SARS- CoV-2诱导α5β1整合素表达增加。最后，虽然血管紧张素转换酶2 ACE 2是病毒进入（内化和融合）宿主细胞的典型受体，其胞外域结合 表面上的病毒刺突蛋白（S蛋白），以促进病毒附着并通过 使用RGD基序的受体介导的内吞作用。由于许多细胞表面整合素也结合RGD，我们和 其他人已经提供了令人信服的证据，证明整联蛋白是病毒的共受体。此外，我们还有 显示talin依赖的整合素活化是SARS-CoV-2感染性所必需的。与我们的结果一致， 先前的研究表明，α5β1和ACE 2参与信号串扰，可能是由相互作用驱动的。 在它们的细胞质尾部的相互作用。基于这些发现，我们假设：（i）整合素α5β1在整合素受体中起作用， 在SARS-CoV-2感染和VaD之间的关联中， COVID-19后既存VaD恶化，（ii）COVID-19感染前、期间或之后接受ATN-161治疗 将稳定血脑屏障的完整性，以在既存血管病变的背景下改善COVID-19神经认知结局 整合素α5β1信号调节感染性，其上调增强了 的BBB。为了研究这些假设，我们提出1）。证明实验性VaD COVID-19发病率和随后的认知能力下降，2）。确定整合素α5β1的治疗潜力 抑制改善VaD后COVID发病率和认知能力下降，3）。确定信号机制 SARS-CoV-2生产性感染和细胞屏障功能失调所需的整合素α5β1。