Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection.

Keywords: Astrocyte; Axon; COVID-19; Cytokine storm; Extracellular vesicles; Immune system; Microglia; Neuron; Oligodendrocyte.

Fig. 1

SARS-CoV-2-induced neurological manifestations. (A) SARS-CoV-2-induced neurologic complications can affect the CNS and PNS. Damage to the brain stem and autonomic nervous systems can lead to respiratory and cardiac dysfunction. Severe COVID-19 patients exhibit systemic inflammation, marked by elevated white blood cells and pro-inflammatory cytokines. Antibodies specific to PNS injury can be detected in blood, including IgG, anti-GM1, anti-GD1a, and anti-GD1b. (B) SARS-CoV-2 binds to ACE2 (shown in figure) or NRP1 receptors, and a serine protease, e.g., TMPRSS2, cleaves the complex, leading to viral internalization. (C) The virus infects sustentacular cells of the nasal epithelium. ACE2, angiotensin-converting enzyme 2; BBB, blood-brain barrier; CNS, central nervous system; GBS, Guillain-Barré Syndrome; NRP1, neuropilin-1; PNS, peripheral nervous system; TMPRSS2, transmembrane serine protease 2. Created, in part, with BioRender.com.

Fig. 2

Neuron-glia homeostasis in the healthy brain. Overview figure of the central nervous system (CNS) under homeostatic conditions. Brain neurons are supported by glia, astrocytes, microglia, and oligodendrocytes. Neurons (light blue): Functioning astrocytes and microglia support signal transmission in healthy neurons, which are wrapped with oligodendrocytes (grey). Blood vessels: Circulating species in blood vessels are separated from the brain by the blood-brain barrier (BBB; pink inset, A). The BBB is comprised of tight junctions between endothelial cells of the vasculature, along with structural reinforcement from the extracellular matrix from the basement membrane and astrocytic foot processes. The BBB regulates what species are permitted to traverse into the central nervous system (CNS). Astrocytes (purple): Contribute structurally to the BBB through astrocyte foot processes, which form a layer against the endothelial basement membrane, defending the brain from invading pathogens. Inset, blue, B: Astrocytes (purple) form tripartite synapses with neurons (light blue) to provide neurotransmitter and metabolic support. Microglia (dark blue): CNS resident immune cells, surveil for potentially harmful agents and clear the CNS of debris by phagocytosis. Inset, green, C: Microglia remodel neuronal circuits by pruning dendritic spines and synapses and promote myelin maintenance and remyelination. Created with BioRender.com.

Fig. 3

Putative SARS-CoV-2-induced disruption of neuron-glia homeostasis. Overview figure of the CNS under SARS-induced pathologic conditions. Neurons (light blue): Excessive inflammation may cause neurons to degenerate. Inset, pink, A: SARS-CoV-2 may also potentially directly invade neurons, triggering apoptosis. Blood vessels: High levels of circulating pro-inflammatory cytokines (blue spheres) damage the BBB; peripheral cytotoxic T cells infiltrate the CNS, further augmenting pro-inflammatory cytokine levels. Circulating SARS-CoV-2 virions can also penetrate the CNS or hijack immune cells to enter. Microbleeds from SARS-CoV-2-induced endothelial dysfunction (asterisks) can also occur, causing CNS damage. Astrocytes (purple and red, activated): SARS-CoV-2 triggers astrogliosis, which raises production of damage-associated molecular pattern molecules, e.g., GFAP. Astrogliosis may also contribute to the breakdown in BBB integrity, e.g., through astrocytic foot processes detachment. Inset, blue, B: SARS-CoV-2 may infect astrocytes, possibly depending on the genotype. Microglia (orange): SARS-CoV-2 induces microgliosis, which elevates microglia-derived pro-inflammatory cytokines (red spheres). Both astrogliosis and microgliosis occur concomitant with neuronal loss. Created with BioRender.com.