- Specific challenges at present regarding Covid-19 and how these are being addressed
Highly pathogenic coronavirus infections are well-established sources of previous epidemics (severe acute respiratory syndrome coronavirus: SARS‐CoV, Middle East respiratory syndrome coronavirus: MERS‐CoV). Of interest, the novel coronavirus named SARS‐CoV‐2, responsible for the current outbreak, shares highly homologous sequence with SARS‐CoV, and is cause of severe respiratory distress, sometimes lethal in humans. While establishing guidelines or empirical therapeutic approaches, we should take advantage of advanced technologies that allow generation and utilization of a number of animal models, in order to understand the precise causes of viral infection in humans and integrate with data emerging from the clinic. Indeed, as recently posted, all around the world, laboratories are rushing to study coronavirus in a number of different transgenic animals (1). These early studies, performed both in mice and non-human primates, show that animals exhibit a relatively mild disease, in spite of a significant viral load (2). Indeed, RT-qPCR revealed a massive infection of the respiratory tract, despite mild clinical symptoms. Yet, Bao and coworkers used the human angiotensin-converting enzyme 2 (hACE2, which is considered the entry receptor for SARS-Cov) transgenic mice and infected them with SARS-CoV-2 confirming prevalent lung involvement (3). These lines of experimental evidence are relevant as they demonstrate the causal relationship between SARS-Cov-2 and pneumonia, reminiscent of Covid19 occurring in humans. Secondly, they provide research laboratories with a tool to explore disease mechanisms, tropism in different organs, and to test novel therapeutics and vaccines at a preclinical level. - Neurological involvement of SARS-CoV2 Unanswered questions
Experimental evidence from previous coronavirus infections demonstrates the ability of these virus subtypes to spread into the CNS, with evidence of particular tropism for brainstem regions. Indeed, neurons in general seem to be vulnerable to SARS-CoV infection, and severe brain dissemination was reported in hACE2 transgenic mice (4). The olfactory bulbs and peripheral nerves have been considered potential routes of entry of SARS-CoV-2 to the CNS, as some coronaviruses have demonstrated the capacity to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. It remains to be answered how this mechanism contributes to respiratory failure in COVID-19 patients (5). In addition, the high expression of human angiotensin-converting enzyme 2 in endothelial cells of small and medium size brain blood vessels raises the alternative possibility of a hematogenic route of spread which could contribute to the recently reported increased incidence of stroke in Covid19 patients. (6). This may potentially have direct implications for stroke treatment approaches. - What you see as the most important next steps to deal with coronavirus across Europe
It is therefore highly important to explore disease models from a translational perspective to anticipate emerging neurological complications and to explore mechanisms of direct or immune-mediated pathogenicity in the short and medium terms. These approaches may pave the way to preventive treatment strategies by blocking viral access to the nervous system, and developing targeted therapies to block replication and direct pathogenic activity of the virus in the nervous system.
Inter-institutional cooperation, public and private parties need to define top-down collaborative strategies so that the appropriate resources (models, chemicals, specific antibodies) can be explored to the maximum, and minimize redundancies.
References
- Nature 579, 183 (2020), doi: 10.1038/d41586-020-00698-x.
- Shan, C. et al. Preprint at Research Square https://doi.org/10.21203/rs.2.25200 (2020).
- Bao, L. et al. Preprint at bioRxiv https://doi.org/10.1101/2020.02.07.939389 (2020).
- Netland et al., J Virol, doi:10.1128/JVI.00737-08 (2008).
- Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Feb 27.doi: 10.1002/jmv.25728.
- Mao L. et al. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1 (2020).
* EAN expert panel:
Antonio Pisani, M.D., Ph.D.
Co-Chair – EAN SP Neuroscience/Translational neurology
Professor of Neurology
Dept. Systems Medicine, University of Rome Tor Vergata,
Rome, Italy
Luís F. Maia, M.D., Ph.D.
Co-Chair – EAN SP Neuroscience/Translational neurology
Neurology Department, Hospital Santo António – CHUP
Porto, Portugal
