Peter Mombaerts, M.D., Ph.D.

Director, Max Planck Research Unit for Neurogenetics, Frankfurt, Germany

Visualizing how SARS-CoV-2 attacks the olfactory system in COVID-19 patients 

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. We reasoned that the neurotropic or neuroinvasive capacity of SARS-CoV-2, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Procuring high-quality fresh tissue samples from the human olfactory mucosa and olfactory bulb has proved challenging, both from living patients and during an autopsy. We have developed a protocol for rapid postmortem bedside sampling of these structures, using an endoscopic endonasal surgical technique that we adapted from skull base surgery. The procedure leaves no visible incisions and enables a rapid response and logistic flexibility in a variety of hospital settings including a ward. Compared to a typical autopsy, the protocol drastically reduces the postmortem interval — in our experience with a cohort of 138 cases, the median was 89 minutes — thereby contributing to preserving the tissue samples in pristine condition. Our cohort included 115 COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19 and that olfactory sensory neurons would become affected without getting infected. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry also afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa. This poorly characterized cell type appears to seal olfactory axon fascicles hermetically from invasion by SARS-CoV-2 virions. We speculate that this barrier may also be effective against some of the many other pathogens that infect the nasal mucosa and could threaten the brain. In conclusion, SARS-CoV-2 appears to be stopped dead in its tracks by several anatomical barriers at vulnerable interfaces, even in extremely weak individuals with an abysmal level of defense who lost the battle.

Bibliografía asociada:

Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb (2021) Cell 184(24):5932-5949. e15. https://doi.org/10.1016/j.cell.2021.10.027

Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients (2022) Neuron 110(23):3919-3935. e6. https://doi.org/10.1016/j.neuron.2022.11.007

Visualising SARS-CoV-2 infection of the lung in deceased COVID-19 patients (2023) EBioMedicine 92:104608. https://doi.org/10.1016/j.ebiom.2023.104608

Protocol for postmortem bedside endoscopic procedure to sample human respiratory and olfactory cleft mucosa, olfactory bulbs, and frontal lobe (2024) STAR Protoc 24;5(1):102831. https://doi.org/10.1016/j.xpro.2023.102831