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4D Nucleome researchers ‘sniff out’ how SARS-CoV-2 causes loss of smell
A young COVID-19 male patient is sniffing a lemon for testing a loss of sense of smell.

When the COVID-19 pandemic began, one of its telltale symptoms was a loss of sense of smell. This loss was not caused by the usual stuffy nose, and for some sufferers it lingered even after the virus was gone. Furthermore, olfactory sensory neurons, the specialized cells responsible for our sense of smell, are rarely infected by the SARS-CoV-2 virus that causes COVID-19. Researchers from the Common Fund’s 4D Nucleome (4DN) program have shed light on this mystery by looking at our DNA. The 4DN program strives to understand the three-dimensional organization of the cell’s nucleus in space and time. In the nucleus, the cell’s DNA, which encodes its genetic instructions, is packaged along with proteins into compact structures called chromatin. Changes in how chromatin is packed into the nucleus can alter gene regulation and cell function.

A team of researchers led by 4D Nucleome grantee Dr. Stavros Lomvardas discovered that nuclear architecture was a missing link between SARS-CoV-2 infection and loss of smell. They observed that genes located in olfactory sensory neurons were downregulated after the SARS-CoV-2 virus infected other nearby cells, meaning the proteins encoded by those genes were produced less often. While some of these genes returned to their usual levels of activity by the tenth day of infection, genes responsible for encoding key proteins in the process of smelling were still downregulated. To explain the persistent gene downregulation, the researchers separated out the nuclei from human olfactory sensory neurons to examine the chromatin architecture. The architecture of key genes related to our sense of smell was disrupted in people infected by SARS-CoV-2, compared to that of uninfected people.

These findings help explain why COVID-19 sufferers may report a decreased sense of smell, even though olfactory sensory neurons are not largely targeted by the virus. It also explains why a loss of smell can continue after viral infection has passed. SARS-CoV-2 can alter the nuclear organization and function of cells it does not infect, resulting in decreased protein production and possibly acting as a “nuclear memory” in cases where loss of smell persists. More studies are needed to identify the molecule (or molecules) that signal for the nuclear reorganization in olfactory sensory neurons, and to explore how the changeable structure of odor perception genes may result in its use as an early indicator of other human conditions.


This page last reviewed on September 1, 2023