Duke Health Referring Physicians


Examining the Mechanism Behind COVID-19-Related Anosmia

Multicenter study sheds light on how, where olfactory cells become infected by virus

Woman smelling a lemon

Patients infected with COVID-19 typically experience sudden disturbances in olfactory function, including anosmia, but the way in which SARS-CoV-2 enters the mucosa and which cell types the virus is able to infect were unknown.

However, findings from a large multicenter study published in July 2020 in Science Advances suggest that the SARS-CoV-2 virus may affect olfaction indirectly through expression of known viral entry genes by non-neuronal cells in the olfactory epithelium. This process is distinct from the mechanism of other upper respiratory viruses such as influenza, which can infect olfactory neurons or their targets in the olfactory bulb.

Using single-cell sequencing data and immunostaining in human and mouse olfactory samples, researchers from Duke, Harvard, and several other institutions identified that the ACE2 protein—which the virus uses to enter cells—is expressed in support cells, stem cells, and perivascular cells. Findings also revealed pervasive expression of ACE2 in dorsally located olfactory epithelial sustentacular cells and olfactory bulb pericytes.

Bradley Goldstein, MD, PhD, a Duke otolaryngologist and sinus specialist who studies olfactory regeneration and repair, was a key contributor to the study. In a separate pre-pandemic paper, his team used single-cell RNA sequencing to analyze gene expression in different cell types of the human olfactory mucosa. The study showed that certain progenitor cells exist in both adult humans and mice and provided the multicenter research group with the only human olfactory dataset available at the time.

“This was a really useful dataset that, in conjunction with some other work in humans involving the lower airway and the lungs as well as ongoing mouse work, allowed us as a collaborative group to more definitively answer the question of how the virus enters and infects olfactory cells,” Goldstein says. “We hope that our work on this new disease helps us learn some things that our field still needs to understand about the olfactory system and, ultimately, identify new therapeutic targets.”

More on Olfactory Supporting Cells

Olfactory supporting cells are an understudied cell type, he adds, but their importance and role in normal olfactory function—particularly when they are damaged—warrant further study. “This collaborative effort has stimulated some interest in studying how important these supporting cells actually are, how they work, and how they contribute to function in this sensory system,” Goldstein says.

One major distinction between COVID-19 olfactory symptoms and the more classic post-viral olfactory disorder is the length of recovery time. “It can take people up to a year or longer to recover from post-viral anosmia, and in many cases, the smell loss is permanent,” Goldstein explains. “With COVID-19, many of the cases are very rapid onset, and many of them do seem to recover fairly quickly over the course of weeks.”

Smell Loss Research and Treatment

Through clinical and translational research, the interdisciplinary team at Duke—including molecular geneticist Hiroaki Matsunami, PhD; immunologists Nicholas Heaton, PhD, and Ashley Moseman, PhD; and head and neck surgeons Ralph Abi Hachem, MD, MSc, David Jang, MD, and Goldstein—hopes to learn more about the mechanisms by which this virus causes smell loss, particularly in the subset of people whose olfactory systems do not recover quickly.

“So far, there aren’t very effective treatments for a lot of forms of smell loss, COVID-19 related or otherwise,” Goldstein says, “but we're hoping that one of the good things to come out of this terrible pandemic is that we're able to learn more about how damage affects the sense of smell and how we might be able to treat that.”

Duke is uniquely positioned in the Carolinas to evaluate and treat patients with olfactory disorders, Goldstein adds. “A lot of otolaryngology departments don't have expertise in smell loss, but we are set up to help evaluate and treat these specific kinds of problems,” he says.

Remaining Questions

Since this study published, the National Institute on Deafness and Other Communication Disorders has requested grant applications on multidisciplinary management approaches to the short- and long-term effects of COVID-19 on sensory systems, including the olfactory system.

“Specifically, they're interested in applications to try and better understand the molecular mechanisms underlying smell loss with this virus,” Goldstein says. “There are some really important basic questions that we still need to understand about how viruses can damage olfactory tissue, how they can lead to sensory loss, and how we can use that information to develop new treatments for these conditions more broadly.”