SARS-CoV-2 proteins directly trigger cough and sneeze reflexes

The team also found that Mpro directly activates sensory neurons, although it produces different reactions. Influenza viruses trigger symptoms through still other routes, Bautista said.

The approach grew from Bautista’s earlier work on neurons involved in touch, itch and pain. Her lab identified TRPA1’s response to wasabi and garlic. It also studied trigeminal nerves, which serve the face and can become inflamed and painful during infection.

In plain terms: infected cells can release viral enzymes that switch on airway nerves through a channel the body uses to sense irritation.

What does this change for drug developers?

Paxlovid targets Mpro and alleviates some COVID-19 symptoms, according to the study. Since the pandemic began, researchers have developed numerous drugs that inhibit PLpro, but none has been approved for COVID.

That remains a preclinical hypothesis. Cultured neurons and mice establish a mechanism, not a treatment effect in patients, and the study did not test PLpro inhibition as a treatment in people.

In plain terms: PLpro is a symptom-control target in principle, not a proven COVID therapy.

How did researchers show that mice sneeze?

To isolate the mechanism, the team purified PLpro and showed that the protein alone activated cultured sensory neurons. When they disabled its catalytic site, the active region that cuts proteins, PLpro had no effect.

They then dabbed mice’s noses with 2 microliters of purified PLpro. Water alone might prompt one sneeze; PLpro produced as many as 30 sneezes in one minute.

Some reviewers still doubted that mice sneeze, so Bautista bought a $75,000 plethysmograph, a device for measuring lung spasms. The PLpro-linked spasms resembled those in other sneezing animals, including guinea pigs.

The team dyed the PLpro solution blue so they could see expelled mucus and measure the amount released in each sneeze. PLpro also caused mechanical hypersensitivity and pain, offering a possible route to infection-related aches.

PLpro from two other coronaviruses, SARS-CoV-1 and MERS, also activated sensory neurons. Together, the cell and mouse results identify a shared route across those three viruses.

In plain terms: the experiments link a viral enzyme to a nerve reflex, while the unusual mouse measurements support the model.

What remains unresolved?

Do coughing and sneezing protect the person or help the virus reach others? Bautista asked: “Who is it helping?” She said the answer may be both, at least early, when expelling virus-laden mucus can prevent infection of other cells.

The direct nerve pathway may also explain some chronic symptoms associated with long COVID, including headache, shortness of breath, persistent cough, sore throat and chest pain. The study used mice and cultured cells, so this human connection remains a possibility, not a demonstrated cause.

Bautista said the paper opens several research questions: what other viral proteins do to nerves, what happens when neurons themselves become infected, and how those neurons contribute to antiviral responses. Her lab still has much more work to do.

The work received support from the National Institutes of Health under grant OD TR01 NS116992 and from the Howard Hughes Medical Institute. Bautista belongs to Berkeley’s Helen Wills Neuroscience Institute.

UC Berkeley co-authors were Sonali Mali, Ricardo Silva, Zhongyan Gong, Michael Cronce, Uyen Vo, Cliff Vuong and Jeffery Cox. Yalda Moayedi of New York University College of Dentistry also contributed.

For now, the practical result is a testable drug target and a new explanation for symptoms; human treatment claims still need clinical evidence.