Microglial Implications in SARS-CoV-2 Infection and COVID-19: Lessons From Viral RNA Neurotropism and Possible Relevance to Parkinson’s Disease

Abstract

Since December 2019, humankind has been experiencing a ravaging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, the second coronavirus pandemic in a decade after the Middle East respiratory syndrome coronavirus (MERS-CoV) disease in 2012. Infection with SARS-CoV-2 results in Coronavirus disease 2019 (COVID-19), which is responsible for over 3.1 million deaths worldwide. With the emergence of a second and a third wave of infection across the globe, and the rising record of multiple reinfections and relapses, SARS-CoV-2 infection shows no sign of abating. In addition, it is now evident that SARS-CoV-2 infection presents with neurological symptoms that include early hyposmia, ischemic stroke, meningitis, delirium and falls, even after viral clearance. This may suggest chronic or permanent changes to the neurons, glial cells, and/or brain vasculature in response to SARS-CoV-2 infection or COVID-19. Within the central nervous system (CNS), microglia act as the central housekeepers against altered homeostatic states, including during viral neurotropic infections. In this review, we highlight microglial responses to viral neuroinfections, especially those with a similar genetic composition and route of entry as SARS-CoV-2. As the primary sensor of viral infection in the CNS, we describe the pathogenic and neuroinvasive mechanisms of RNA viruses and SARS-CoV-2 vis-à-vis the microglial means of viral recognition. Responses of microglia which may culminate in viral clearance or immunopathology are also covered. Lastly, we further discuss the implication of SARS-CoV-2 CNS invasion on microglial plasticity and associated long-term neurodegeneration. As such, this review provides insight into some of the mechanisms by which microglia could contribute to the pathophysiology of post-COVID-19 neurological sequelae and disorders, including Parkinson’s disease, which could be pervasive in the coming years given the growing numbers of infected and re-infected individuals globally.

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

“…SARS-CoV-2 has a definite brain neurotropism via its ability to bind to the angiotensinconverting enzyme 2 (ACE2) receptor on the cell membranes of neurovascular unit brain endothelial cells, neurons (both excitatory and inhibitory), and neuroglia, which include the microglia cells, astrocytes, and oligodendrocytes [94][95][96]. Additionally, hyper-activation of the immune system and an excessive aberrant cytokine storm with excessive amounts of PCC in an attempt to eradicate the SARS-CoV-2 which causes COVID-19 may trigger autoimmune responses and autoimmune disease.…”

“…Autoimmunity induced by SARS-CoV-2 tropism to both peripheral organs and the central nervous system are both possible. Certain mechanisms are currently thought to be involved and include molecular mimicry between viral SARS-CoV-2 and host self-antigen epitopes, breakdown of immune tolerance (possibly due to excessive fatigue, and even burnout of the adaptive immune systems due high sustained viral loads, which result in lymphopenia and an increase in the neutrophil/lymphocyte ratio), non-specific bystander activation, epitope spreading, super-antigen presentation, and even stimulation of inflammasome platforms [94][95][96][97][98]. Once SARS-CoV-2 enters the cell via its S-1 spike protein, it will hijack the host cells organelles, nucleus, and its reproductive machinery to generate as many progeny virions as it can, while leaving the infected host cell disabled or damaged significantly and may even cause the host cell to die along with liberating a great amount of fragmented host cell self-antigens (Ag).…”

Did the COVID-19 Pandemic Increase the Incidence of Acute Macular Neuroretinopathy?

“…Importantly, microglia and retinal glial Müller (RMG) cell interactions could also explain the location of AMN lesions in the area of Z-shaped RMG cells [ 42 ]. Therefore, we speculate that this significant increase in AMN could be due to an autonomous system deregulation of choroidal blood flow caused by SARS-CoV-2 and/or inappropriate activation of the resident microglia [ 43 ].…”

Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer’s Disease, Parkinson’s Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome

“…long-COVID patients persistently suffer from unacceptable neurological symptoms such as brain fog, fatigue, depression, and anxiety [ 93 , 94 ]. The question remains whether in long-COVID patients, microglia are hyperactivated and become proinflammatory, and if this process is accelerated by activation of the NLRP3 inflammasome [ 95 ]. If so, an inhibitor of the NLRP3 inflammasome could become an effective therapeutic for long-COVID.…”