July 28, 2020 by Sam Bazzi
Since our lab has begun studies on COVID-19 during the past month, I must apologize to my readers for not posting as frequently. It’s been very exciting to finally get back in the lab regularly, but I only wish that it was under more pleasant circumstances (and without N95 face bruises). Nonetheless, I will be posting again regularly now that we’ve gotten into the rhythm of processing samples.
This week, I was thinking about viral propagation in the CNS. I’ve written previously about how different human coronavirus (HCoV) strains have been demonstrated to exist in the CNS, but until today I have not read any material on how they propagate. There is currently a lot of speculation about the nature of neurological symptoms in COVID-19, but little evidence we can cite to definitively identify the cause. Some believe SARS-CoV-2 induces the cytokine storm, which damages neural tissues indirectly while others believe in direct viral infiltration into (and propagation within) the brain. It is too early to say which of these hypotheses – if not both – is more correct, but there is some evidence that SARS-CoV-2 can invade and replicate within human neurons in vitro (see previous blog post about BrainSphere model).
I decided to dig further into the topic of viral propagation in the CNS, and found one report in the Journal of Virology, published in 2018 by the lab of Dr. Pierre Talbot, whose name has been quite common in the references of previous blog posts. The authors wanted to determine whether or not human coronaviruses could propagate directly from neuron to neuron. Using C57BL/6 mice infected with aerosol droplets containing HCoV strain OC43, Dubé et al. found that HCoV OC43 enters the CNS through neuroepithelium and begins propagating in the olfactory bulbs. Using immunohistochemistry (IHC), they found that viral antigens were detected in the olfactory bulb at 3 days post-infection (dpi) and increased quantities detected at 4 dpi (Dubé et al. 2018). Additionally, they found that at 4 dpi, the virus had already spread to the hippocampus, brain stem, and spinal cord. Notably, they did not find any viral replicates in the blood, so they hypothesized that the virus spreads via axons. Using IHC, they stained OC43 nucleocapsid protein in mice that were intracranially infected. They determined that the nucleocapsid protein was highly associated with ꞵIII-tubulin+-axons in hippocampus, diencephalon, and cortex. They then went on to do some sophisticated in vitro studies using confocal microscopy to study the dynamics of the spike platforms at the axons and how different cell culture conditions affect propagation – which I recommend you read yourself, as it is really interesting and a little too much to describe in one blog post!
I think that this study and early in vitro studies on SARS-CoV-2 provide a compelling case for the hypothesis of direct HCoV entry and propagation within the CNS. The evidence needed to establish that this is the case in COVID-19 will have to involve post-mortem studies in infected patients that suffered neurological symptoms. This work would allow us to determine if the virus is located in sensory olfactory neurons and propagates to other parts of the brain, and perhaps allow us to study whether or not early neurological symptoms like anosmia may correlate with worse neurological symptoms later on. This is not to say that indirect methods of CNS damage such as the cytokine storm do not play a role, but there has been a lot less exciting research on how SARS-CoV-2-induced cytokines affect neurological symptoms.
Written by: Sam Bazzi
Edited by: Esther Melamed
7/28/2020
References
Dubé, M., Le Coupanec, A., Wong, A. H., Rini, J. M., Desforges, M., & Talbot, P. J. (2018). Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. Journal of virology, 92(17).
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