Abstract
SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.
Highlights
SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019
SARS-CoV-2 infection starts in the lungs, inducing the severe acute respiratory syndrome regularly associated with neurological symptoms
central nervous system (CNS) involvement has been a topic of extensive study, little attention has been paid to the possible role of brainstem infection in organ failure
Summary
SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. The low representation of SARS-CoV-2 in CSF may be related to a poor ability to bud in this tissue as observed for measles virus (MeV) or to any limitation to invade the brain in the most severe respiratory cases which represent the large majority of the samples. The S1 fragment of the Spike protein cleaved by furin can bind to Neuropilin-1, which is abundantly expressed at the surface of endothelial and epithelial cells
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