Researchers discover how the COVID virus triggers sneezing and coughing

UC Berkeley researchers used mice to demonstrate for the first time that viral proteins from SARS-CoV-2 can directly stimulate sensory neurons responsible for sneezing, coughing and pain. This discovery emerged after lab members, including Bautista, experienced pandemic symptoms firsthand, prompting a five-year investigation into how viruses provoke these reactions. The study, led by doctoral student Sonali Mali and published in Neuron, reveals that viral proteins bypass immune-mediated inflammation to directly activate nociceptors in the airways.

The team identified the viral protease PLpro as the specific trigger that binds to sensory neuron surfaces, activating the TRPA1 ion channel—the same channel stimulated by wasabi and garlic—to induce pain, sneezing and airway inflammation. Experiments showed purified PLpro alone was sufficient to activate cultured sensory neurons, while eliminating its enzymatic activity abolished this effect. Mice exposed to PLpro exhibited up to 30 sneezes per minute, far exceeding the response to water, confirming direct neural activation.

Researchers also found that another viral protease, Mpro, directly triggers sensory neurons but produces different reactions than PLpro. The study suggests these proteases may contribute to chronic conditions in long COVID, including headache, persistent cough and chest pain. Bautista noted that drugs targeting Mpro, such as Paxlovid, alleviate some symptoms, and inhibitors of PLpro—though not yet approved—could similarly treat viral symptoms and limit spread.

The findings challenge the assumption that symptoms like coughing and sneezing are solely protective reflexes, raising questions about whether they primarily benefit the host or the virus. Bautista’s lab plans to explore how other viruses and viral proteins interact with the nervous system, including whether neurons themselves can be infected and how they contribute to antiviral responses. The work was funded by NIH and HHMI, with co-authors from UC Berkeley and NYU.