Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.

Keywords: ACE2; COVID-19; Cerebrovascular disease; Coronavirus (CoV); Guillain-Barré syndrome (GBS); Multiple sclerosis; Nervous system; Neuropathogenesis; SARS-CoV-2.

Fig. 1

Schematic representation showing the possible mechanisms underlying neurological consequences of COVID-19. CBF, cerebral blood flow; CPP, cerebral perfusion pressure

Fig. 2

a Human cells that express ACE2 receptors in the CNS. b Brain areas that express ACE2 receptors. c Binding of SARS-CoV-2 to a neuron (ACE2 receptors on a medullary neuron binding to the SPIKE protein on SARS-CoV-2)

Fig. 3

Schematic representation showing pathomechanisms of nervous system injury caused by coronaviruses (CoV). ACE2, angiotensin-converting enzyme 2; BBB, blood–brain barrier; IL, interleukin; MHC, major histocompatibility complexes; SIRS, systemic inflammatory response syndrome

Fig. 4

Transsynaptic viral spread: (a) Spread via the transcribrial route: Coronavirus (CoV) has been shown to spread via the transcribrial route from the olfactory epithelium along the olfactory nerve to the olfactory bulb within the CNS. (b) Spread via transsynaptic transfer: CoV has been shown to spread retrograde via transsynaptic transfer using an endocytosis or exocytosis mechanism and a fast axonal transport (FAT) mechanism of vesicle transport to move virus along microtubules back to neuronal cell bodies. Mechanisms of spread across the BBB: (c) Leukocyte infection: Infected leukocytes can cross the BBB to infect the CNS through the Trojan horse mechanism. (d) Endothelial infection: Infected vascular endothelial cells have been shown to spread SARS-CoV-2 to glial cells in the CNS

Fig. 5

Putative mechanisms underlying SARS-CoV-2 neuropathogenesis: SARS-CoV-2 neuropathogenic effects are likely multifactorial, including, involvement of the peripheral nervous system (PNS) and muscle, direct neuroinvasion of the central nervous system (CNS), manifestations of systemic disease, as well as through a post-infectious, immune-mediated mechanism. MOF: multi-organ failure. Phi (φ) denotes direct evidence of viral invasion (RT-PCR + , biopsy); star (★) denotes CNS inflammation (CSF pleocytosis and proteinoracchia) with no evidence of direct viral infection of CNS