Murine-β-coronavirus-induced neuropathogenesis sheds light on CNS pathobiology of SARS-CoV2

Abstract

The pandemic caused by SARS-CoV-2 has caused widespread infection and significant mortality across the globe. Combined virology perspective of SARS-CoV-2 with a deep-rooted understanding of pathophysiological and immunological processes underlying the clinical manifestations of COVID-19 is of prime importance. The characteristic symptom of COVID-19 is respiratory distress with diffused alveolar damage, but emerging evidence suggests COVID-19 might also have neurologic consequences. Dysregulated homeostasis in the lungs has proven to be fatal, but one cannot ignore that the inability to breathe might be due to defects in the respiratory control center of the brainstem. While the mechanism of pulmonary distress has been documented in the literature, awareness of neurological features and their pathophysiology is still in the nascent state. This review makes references to the neuro-immune axis and neuro-invasive potential of SARS-CoV and SARS-CoV2, as well as the prototypic H-CoV strains in human brains. Simultaneously, considerable discussion on relevant experimental evidence of mild to severe neurological manifestations of fellow neurotropic murine-β-CoVs (m-CoVs) in the mouse model will help understand the underpinning mechanisms of Neuro-COVID. In this review, we have highlighted the neuroimmunopathological processes in murine CoVs. While MHV infection in mice and SARS-CoV-2 infection in humans share numerous parallels, there are critical differences in viral recognition and viral entry. These similarities are highlighted in this review, while differences have also been emphasized. Though CoV-2 Spike does not favorably interact with murine ACE2 receptor, modification of murine SARS-CoV2 binding domain or development of transgenic ACE-2 knock-in mice might help in mediating consequential infection and understanding human CoV2 pathogenesis in murine models. While a global animal model that can replicate all aspects of the human disease remains elusive, prior insights and further experiments with fellow m-β-CoV-induced cause-effect experimental models and current human COVID-19 patients data may help to mitigate the SARS-CoV-2-induced multifactorial multi-organ failure

Multi-Organ Histopathological Changes in a Mouse Hepatitis Virus Model of COVID-19

“…Laboratory MHV strains have been broadly studied to identify harmful coronavirus factors and elucidate host mechanisms of antiviral pathogenicity (see, [65][66][67][68] and references therein). The major MHV viruses used are MHV-3, MHV-A59, MHV-JHM, and MHV-S.…”

Azadirachta indica A. Juss bark extract and its Nimbin isomers restrict β-coronaviral infection and replication

“…The in vivo model used was m-CoV-RSA59 infected mice, which targets the CNS and liver, two clinically relevant organ targets which are associated with severe COVID-19 ( Chakravarty and Das Sarma, 2021 ; Mao et al, 2020 ) ( Saviano et al, 2021 ). Numerous neurologic manifestations of COVID-19 have been documented, including encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, loss of smell (anosmia) and taste (ageusia), difficulty concentrating, altered consciousness, confusion, neuropsychiatric disorders, focal seizures, and Guillain-Barre syndrome.…”

“…Related murine-β-Coronaviruses (m-β-CoVs) facilitate studying conserved mechanisms of COVID pathobiology. MHV-1 produces a SARS-CoV-like lethal disease ( De Albuquerque et al, 2006 ; Hua et al, 2018 ), and neurotropic m-CoV-MHV-A59 or its spike protein targeted recombinant strain RSA59 infection inC57BL/6 mice initiates a biphasic disorder from acute meningoencephalomyelitis to chronic demyelination ( Chakravarty and Das Sarma, 2021 ; Das Sarma, 2010 , 2014 ). The consequences of SARS-CoV-2 neuro-infection as reported may be inferred from m-CoV-RSA59-induced neuro-COVID ( Chakravarty and Das Sarma, 2021 ; Mao et al, 2020 ).…”

Neurotropic Virus-Induced Meningoencephalomyelitis

“…There is also evidence suggesting coronaviruses such as α-CoVs (NL63 and 229E) and the β-CoVs (OC43, HKU1) being positive-sense single-stranded, enveloped RNA viruses, Neurotropic Virus-Induced Meningoencephalomyelitis DOI: http://dx.doi.org/10.5772/intechopen.102674 can induce numerous neurological manifestations along with systemic inflammations in humans. A very recent outbreak of human β coronavirus SARS-CoV-2 is primarily known for its ARDS and paramount evidence suggest that it may enter the brain via olfactory route or can enter through the lung brain axis or gut-brain axis and is also known to cause meningitis, encephalitis, and demyelination [102][103][104].…”