In the first two decades of the 21st century, there have been three outbreaks of severe respiratory infections caused by highly pathogenic coronaviruses (CoVs) around the world: the severe acute respiratory syndrome (SARS) by the SARS-CoV in 2002–2003, the Middle East respiratory syndrome (MERS) by the MERS-CoV in June 2012, and Coronavirus Disease 2019 (COVID-19) by the SARS-CoV-2 presently affecting most countries In all of these, fatalities are a consequence of a multiorgan dysregulation caused by pulmonary, renal, cardiac, and circulatory damage; however, COVID patients may show significant neurological signs and symptoms such as headache, nausea, vomiting, and sensory disturbances, the most prominent being anosmia and ageusia. The neuroinvasive potential of CoVs might be responsible for at least part of these symptoms and may contribute to the respiratory failure observed in affected patients. Therefore, in the present manuscript, we have reviewed the available preclinical evidence on the mechanisms and consequences of CoVs-induced CNS damage, and highlighted the potential role of CoVs in determining or aggravating acute and long-term neurological diseases in infected individuals. We consider that a widespread awareness of the significant neurotropism of CoVs might contribute to an earlier recognition of the signs and symptoms of viral-induced CNS damage. Moreover, a better understanding of the cellular and molecular mechanisms by which CoVs affect CNS function and cause CNS damage could help in planning new strategies for prognostic evaluation and targeted therapeutic intervention.
The evidence examined in the present review highlights the long-known but currently little-considered ability of CoVs to invade the CNS and cause neurological diseases. It also shows, however, that most of our knowledge of CoV neurovirulence derives from studies performed in rodents infected with MHVs or HCoV-OC43. On the other hand, the information on the new human CoVs is much more limited. Many basic questions concerning the neurobiology of these new viruses still need to be addressed in experimental animals, and major clinical points concerning CoVs infections in human patients remain to be urgently clarified for SARS-CoV-2 in light of the devastating health consequences of the ongoing COVID-19 pandemic. Reliable animal models are critical to successfully address these issues (Natoli et al., 2020). In fact, both MERS and SARS can hardly be replicated in rodents, and transgenic animals overexpressing the receptors for their causative viruses display a non-physiological distribution pattern of CoV receptors in the CNS which does not faithfully replicate the neurobiology of these viruses (McCray Jr. et al., 2007; Agrawal et al., 2015). Moreover, even in hACE2 overexpressing mice, no evidence of CNS invasion was detected upon experimental infection with SARS-CoV-2 (Bao et al., 2020); thus, better animal models of SARS-CoV-2 neuroinvasion and/or different experimental conditions for neuroinfection are also needed.
Many questions regarding the neurological consequences of COVID-19 in humans are still unanswered. For instance, it is currently unknown whether the neurological signs described in COVID-19 patients are a consequence of a direct SARS-CoV-2 CNS infection; however, the fact that SARS-CoV-2 genome has been isolated from the CSF of a COVID-19 patient (Zhou et al., 2020) suggests direct viral neuroinvasion. Further attempts to isolate SARS-CoV-2 from the CSF, and autopsies of COVID-19 victims may shed some light. In addition, knowing whether the encephalopathy occurring during the acute phase of the disease leads to long lasting sequelae such as chronic epilepsy or cognitive impairment would be critical for rigorous prognostic evaluation; however, we presently don't know whether SARS-CoV-2 establishes latent infections that could either reactivate or trigger chronic neurological disorders. Shared procedures for early identification of COVID-19 patients at high risk of neurological involvement are essential. In order to better define the extent and pathomechanism of CNS damage, special attention should be given to signs and symptoms that could suggest brainstem impairment. These may then prompt further diagnostic investigations with auditory brainstem responses, neuroimaging tools, or CFS analysis, as recently suggested (Ogier et al., 2020). Studies aiming to better characterize the immunological mechanisms responsible for disease pathogenesis could additionally provide solid conceptual basis for the rational use of immune modulators such as the anti-IFN-γ emapalumab, the IL-1 antagonist anakinra, and the two monoclonal antibodies targeting the IL-6 pathway sarilumab and tocilizumab. All these drugs, potentially representing targeted therapeutic interventions to prevent or dampen neuroinflammation in COVID-19 patients, are currently under active investigation.
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