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.

抽象的 迅速出现的证据表明血管性痴呆 (VaD) 与 我们推测，COVID-19 的发病率、发病率和后认知能力下降与脑血管病理有关。 VaD 和其他病理生理学特征，例如血脑屏障 (BBB) 破坏和脑功能减少 血流可能直接导致 VaD 和 COVID-19。多项证据支持这一假设。 首先，我们证明了 SARS-CoV-2 与血管整合素 α5β1 受体结合来感染细胞，即 我们还发现相同的受体与脑缺血（中风）模型和慢性双侧血脑屏障破坏有关。 颈动脉狭窄 (BCAS)，模拟 VaD 的病理生理学方面，例如脑血减少 血流、血脑屏障破坏、神经炎症、白质损伤和认知能力下降 其次，整合素 α5β1 是。 中风后脑血管系统中的脑血管系统以年龄依赖性方式大幅上调（老年>年轻） BCAS，以及通过临床验证的整合素 α5β1 五肽抑制剂 ATN-161 抑制该受体 减少这些模型中的 BBB 破坏和认知障碍。第三，SARS-CoV-2 感染也会增加。 第四，初步结果表明 SARS-CoV-2 体内整合素 α5β1 表达并破坏 BBB。 与 BCAS 或单独感染相比，BCAS 后感染进一步增加发病率并加速脑血管 第五，ATN-161 在体外和体内抑制 SARS-CoV-2 感染并预防 SARS- 最后，尽管血管紧张素转换酶 2 被 CoV-2 诱导，α5β1 整合素表达增加。 (ACE2) 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 表面的病毒刺突蛋白（S-蛋白）可促进病毒附着并通过以下途径进入宿主细胞： 由于许多细胞表面整合素也结合 RGD，我们和使用 RGD 基序进行受体介导的内吞作用。 其他人提供了令人信服的证据表明整合素是病毒的共同受体。 研究表明，talin 依赖性整合素激活是 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 ACE2 参与信号串扰，可能是由相互驱动的 基于这些发现，我们发现 (i) 整合素 α5β1 发挥着重要作用。 SARS-CoV-2 感染与 VaD 之间的关联具有重要的年龄依赖性致病作用 COVID-19 后原有 VaD 恶化，(ii) 在 COVID-19 感染之前、期间或之后进行 ATN-161 治疗 将稳定 BBB 完整性，以改善已有血管背景下的 COVID-19 神经认知结果 痴呆症，以及 (iii) 整合素 α5β1 信号传导调节感染性，其上调会加剧 为了研究这些假设，我们建议 1) 加深实验性 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)。 SARS-CoV-2 有效感染和细胞屏障功能失调所需的整合素 α5β1。