Center for Neurotherapeutics Discovery, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Adv Neurobiol. 2024;37:423-444. doi: 10.1007/978-3-031-55529-9_24.
Microglia, brain-resident innate immune cells, have been extensively studied in neurodegenerative contexts like Alzheimer's disease. The Coronavirus disease 2019 (COVID-19) pandemic highlighted how peripheral infection and inflammation can be detrimental to the neuroimmune milieu and initiate microgliosis driven by peripheral inflammation. Microglia can remain deleterious to brain health by sustaining inflammation in the central nervous system even after the clearance of the original immunogenic agents. In this chapter, we discuss how pulmonary infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) can lead to neurovascular and neuroimmune inflammation causing the neurological syndrome of post-acute sequelae of COVID-19 (PASC). Further, we incorporate lessons from the Human Immunodeficiency Virus' (HIV's) effects on microglial functioning in the era of combined antiretroviral therapies (cART) that contribute to HIV-1 associated neurocognitive disorders (HAND). Finally, we describe roles for mixed lineage kinase 3 (MLK3) and leucine-rich repeat kinase (LRRK2) as key regulators of multiple inflammatory and apoptotic pathways important to the pathogenesis of PASC and HAND. Inhibition of these pathways provides a therapeutically synergistic method of treating both PASC and HAND.
小胶质细胞是驻留于脑内的固有免疫细胞，在阿尔茨海默病等神经退行性疾病的相关研究中被广泛研究。2019 年冠状病毒病（COVID-19）大流行突显了外周感染和炎症如何对神经免疫环境有害，并引发由外周炎症驱动的小胶质细胞增生。即使清除了最初的免疫原性物质，小胶质细胞仍能通过在中枢神经系统中持续引发炎症而对大脑健康造成损害。在本章中，我们将讨论严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）肺部感染如何导致血管和神经免疫炎症，从而导致 COVID-19 后急性后遗症的神经系统综合征（PASC）。此外，我们将结合人类免疫缺陷病毒（HIV）在联合抗逆转录病毒疗法（cART）时代对小胶质细胞功能的影响，这些影响导致了 HIV-1 相关神经认知障碍（HAND）。最后，我们描述了混合谱系激酶 3（MLK3）和富含亮氨酸重复激酶 2（LRRK2）作为多种炎症和凋亡途径的关键调节剂的作用，这些途径对 PASC 和 HAND 的发病机制很重要。抑制这些途径为治疗 PASC 和 HAND 提供了一种具有治疗协同作用的方法。
