Few of Covid-19’s peculiarities have aroused as much interest as anosmia, the abrupt loss of odor that has become a well-known hallmark of the disease. Covid patients lose this sense even without a stuffy nose; the loss can cause the food to taste like cardboard and coffee to smell harmful, and sometimes continue after other symptoms have disappeared.
Researchers are now beginning to uncover the biological mechanisms that have been a mystery: The neurons that detect odors lack the receptors that the coronavirus uses to penetrate cells, prompting a long debate about whether they can get infected.
Insights gained from new research may shed new light on how coronavirus can affect other types of brain cells, leading to conditions such as “brain fog”, and possibly help explain the biological mechanisms behind long Covid – symptoms that linger for weeks or months after initial infection.
The new work, along with previous research, debates whether coronavirus infects the nerve cells that detect odors: It does not. But the virus attacks other supporting cells lining the nasal cavity, the researchers found.
The infected cells secrete viruses and die, while immune cells flood the region to fight the virus. The subsequent inflammation causes havoc on odor receptors, proteins on the surface of the nerve cells in the nose that detect and transmit odor information.
The process alters the sophisticated organization of genes in these neurons, and short-circuits them essentially, the researchers reported.
Their paper significantly promotes the understanding of how cells that are critical for the sense of smell are affected by the virus, despite not being directly infected, said Dr. Sandeep Robert Datta, associate professor of neurobiology at Harvard Medical School, who was not involved in the study.
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“Obviously, indirectly, if you affect the support cells in the nose, a lot of bad things happen,” said Dr. Datta. “The inflammation in the adjacent cells triggers changes in the sensory neurons that prevent them from functioning properly.”
In fact, many complications of Covid appear to be caused by the friendly fire of the immune system, as it responds to infection by flooding the bloodstream with inflammatory proteins called cytokines, which can damage tissues and organs.
“This may be a general principle: that much of what the virus does to us is a consequence of its ability to generate inflammation,” said Dr. Datta.
The new study is based on research conducted at the Zuckerman Institute and Irving Medical Center at Columbia University in New York; New York University Grossman School of Medicine; Icahn School of Medicine at Mount Sinai in New York; Baylor Genetics in Houston; and the School of Medicine at the University of California, Davis. The research was published online in Cell in early February.
The researchers examined gold hamsters and human tissue samples from 23 patients who succumbed to Covid. After the hamsters became infected with the original coronavirus, the researchers tracked the damage to their olfactory systems over time.
“How do you know a golden hamster has lost its sense of smell? You do not feed it for hours and then bury Cocoa Puffs in its bedding,” said Benjamin tenOever, professor of microbiology at NYU Langone Health and author of new research. Hamsters that can smell, finds the grains in seconds.)
The virus did not invade neurons, the researchers learned, only those cells that play supporting roles in the olfactory system. But it was enough to alter the function of the nearby neurons, leading to loss of odor.
The immune response altered the architecture of genes in the neurons and disrupted the production of odor receptors, said Marianna Zazhytska, a postdoctoral fellow at the Zuckerman Institute and one of the paper’s first authors along with a graduate student, Albana Kodra.
“It’s not the virus itself that is causing all this reorganization – it’s the systemic inflammatory reaction,” said Dr. Zazhytska. “The nerve cells do not host the virus, but they do not do what they did before.”
The ability of olfactory receptors to send and receive messages is impaired. But the neurons do not die, and then the system can recover after the disease has disappeared.
Previous work at the Zuckerman Institute has shown that neurons that detect odors have complex genomic organizational structures that are essential for the creation of odor receptors, and the receptor genes communicate very intensively with each other, said Stavros Lomvardas, one of the paper’s similar authors.
“We saw early on that after infection, the genomic organization of these neurons changes completely – they are unrecognizable compared to how they normally are,” said Dr. Lomvardas.
“There is a signal released from the infected cells that is received by neurons that normally detect odors and tells them to rearrange and stop the expression of odor receptor genes,” he said.
He suggested that this may represent an evolutionary adaptation that offers some form of antiviral resistance and whose main purpose may be to prevent the virus from penetrating the brain. “It was a relief for us,” he said. “That was good news.”