Researchers have discovered that SARS-CoV-2 proteins directly stimulate sensory nerves to trigger sneezing, coughing, and pain, identifying a mechanism that bypasses the body’s inflammatory response.
Published in the November 13 issue of the journal Neuron, the study provides the first evidence that viral proteins can activate these nerves directly to promote respiratory symptoms.
The research, conducted at UC Berkeley, centers on viral proteases known as PLpro (papain-like protease) and Mpro (main protease). These proteins are produced when the virus infects cells. Once the virus kills the host cells, these proteases are released into the body, where they stimulate a subset of sensory nerves called nociceptors found throughout the airways.
Previously, the prevailing scientific view held that respiratory symptoms were primarily the result of inflammatory mediators released by infected epithelial and immune cells acting on sensory neurons. This new research indicates that a direct route of activation also exists. According to the study, this process may help explain certain chronic conditions associated with long COVID, including persistent cough, chest pain, shortness of breath, sore throat, and headache.
Diana Bautista, a Berkeley professor of molecular and cell biology and a Howard Hughes Medical Institute investigator, said that while drugs like Paxlovid target Mpro, focusing on PLpro could provide additional therapeutic benefits. Numerous drugs targeting PLpro were developed following the start of the pandemic, though none have been approved for COVID-19 treatment.
“We think that these protease inhibitors that people spent a lot of time and money developing could be important not just for preventing viral replication,” said Diana Bautista.
“They could also help treat symptoms like coughing, which could limit viral spread, and potentially prevent severe COVID-19 in individuals who are susceptible,” said Diana Bautista.
The research team also observed that Mpro triggers sensory neurons, though it produces different reactions than PLpro. Bautista emphasized that the interaction between pathogens and the nervous system is complex, noting that researchers are still working to understand the distinct molecular and cellular routes by which various viruses and bacteria drive symptoms.
“There are many modes by which viral and bacterial infections can act in our bodies — there are distinct molecular and cellular routes of triggering this type of airway hyper-reactivity,” said Diana Bautista.
“With so many emerging pathogens, we’re just starting to understand how they work. So far, it looks like they can drive symptoms through both the immune system and the nervous system, using different molecular mechanisms. I think we have a lot to figure out,” said Diana Bautista.
