Puzzle Solved? How the SARS-CoV-2 Virus Shuts Down the Sense of Smell
Puzzle Solved? How the SARS-CoV-2 Virus Shuts Down the Sense of Smell
Clever experiments with live hamsters and human cadavers
Image from Zazhytska et al., Cell 2022
A prominent feature of COVID-19 illness—at least the pre-omicron variants—was the high frequency of transient or permanent smell loss. The loss appeared to be more severe than that seen during “regular” flu; it could be severe even while other symptoms were relatively mild.
This led to a lot of on-the-fly clinical data gathering, often with the hope that smell loss could be used as a population-wide diagnostic screener (a hope I believe was statistically delusional).
It also led to a search for the physiological mechanism underlying the sensory pathology. And here is where a puzzle emerged.
Turns out it is the sustentacular (supporting) cells of the nasal neuroepithelium that get infected, not the olfactory sensory neurons themselves. That’s because the non-sensory cells express the ACE2 protein the SARS virus uses to gain entry, while the sensory neurons do not. Thus the puzzle: how does infection of non-sensory cells in the nose lead to dysfunction in the sensory neurons?
A solution to the problem is presented in a paper by Zazhytska et al. published yesterday in Cell. They did extensive RNA sequencing of nasal tissues in hamsters, both healthy ones and others experimentally inoculated with the virus, and yet others treated with virus-free serum from infected animals. They also examined autopsy nasal tissue from people with and without COVID-19.
Their key conclusions:
Here we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. (. . . / . . .)
Thus, the most likely explanation for COVID-19 induced anosmia is the non-cell autonomous, widespread, and persistent downregulation of OR and OR signaling genes. (. . . / . . .)
Our data provide a potential mechanism by which SARSCoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.
My fluency in cell and molecular biology, like my grasp of French, is tourist-level at best. Thus I can only provide an impressionistic account of Zazhytska et al.’s findings. They describe how the virus indirectly disrupts the process by which the olfactory sensory neuron (OSN) reads its DNA to produce olfactory receptor proteins—the structures that catch incoming odorant molecules.
Specifically,
OR gene clusters from multiple chromosomes converge to OSN-specific genomic compartments, which facilitate stable and singular OR transcription . . .
and according to the authors, this process gets screwed up by a yet-to-be-identified circulating factor associated with viral infection (not by the virus particle itself). They believe it is this wrench in the genetic machinery that produces smell loss.
The authors admit their evidence is indirect yet based on strong inference. They also note that they did not identify the circulating molecule(s) that set off this disruption inside the olfactory neurons.
Nevertheless, this is a bravura piece of work that opens the door to an entirely new line of research on post-infection smell loss in general.
Marianna Zazhytska, Albana Kodra, Daisy A. Hoagland, Justin Frere, John F. Fullard, Hani Shayya, Natalie G. McArthur, Rasmus Moeller, Skyler Uhl, Arina D. Omer, Max E. Gottesman, Stuart Firestein, Qizhi Gong, Peter D. Canoll, James E. Goldman, Panos Roussos, Benjamin R. tenOever, Jonathan B. Overdevest, and Stavros Lomvardas. (2022). Non-cell autonomous disruption of nuclear architecture as a potential cause of COVID-19 induced anosmia. Cell (in press).