Infectious Diseases

Abstract

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.

Keywords: Coronavirus disease 2019; Human immunodeficiency virus; Human immunodeficiency virus-associated neurocognitive disorder; Inflammation; Leucine-rich repeat kinase 2; Microglia; Mixed lineage kinase 3; Postacute sequelae of coronavirus disease 2019; Severe acute respiratory syndrome coronavirus 2.

Fig. 24.1

Mechanistic overview of how SARS-CoV-2 infection leads to post-acute sequelae of COVID-19. (Figure was created on www.Biorender.com)

Fig. 24.2

Cellular and molecular representation of post-acute sequelae of COVID-19 and therapeutic interventions. (a) Cellular mechanisms in the brain during PASC. (b) MLK3 and LRR2 signaling in microglia during PASC and therapeutic potential. (Figure created on Biorender.com)

Fig. 24.3

Cellular and molecular representation of post-acute HIV-associated neurocognitive disorder and therapeutic interventions. (a) Cellular mechanisms in the brain during HAND. (b) MLK3 and LRR2 signaling in microglia during HAND and therapeutic potential. (Figure created on Biorender.com)