Summary:
Neuroscientists have discovered that SARS-CoV-2 viral proteins directly activate pain-sensing nerves in the airways to trigger sneezing, coughing, and body aches, overturning the long-held view that symptoms stem solely from immune inflammation.
The study shows that the viral enzyme PLpro activates the wasabi-sensing TRPA1 receptor on sensory neurons, offering new therapeutic targets for acute viral symptoms and long COVID.
Key Facts:
- Direct Neural Hijacking: Rather than relying solely on secondary immune inflammation, viral proteases released by dying infected cells, specifically papain-like protease (PLpro) and main protease (Mpro), directly stimulate airway sensory nociceptors.
- The “Wasabi Receptor” Pathway: Purified SARS-CoV-2 PLpro triggers sneezing, coughing, and mechanical pain by enzymatically activating the TRPA1 ion channel, the exact same sensory receptor activated by pungent compounds in wasabi and garlic.
- Therapeutic Potential Beyond Replication: Existing experimental drugs designed to block PLpro could potentially double as treatments to suppress severe coughing, reduce viral transmission, and alleviate persistent long COVID pain and respiratory symptoms.
Source: UC Berkeley / Neuron
For decades, textbooks have explained the misery of respiratory infections, the racking coughs, relentless sneezing, headaches, and full-body aches, as collateral damage from the immune system. According to conventional wisdom, infected airway cells and responding immune cells release a storm of inflammatory mediators that secondarily irritate nearby nerve endings.
Now, a study published in the journal Neuron reveals that coronaviruses do not wait for the immune system to sound the alarm; their viral proteins directly hijack the peripheral nervous system.
Led by Dr. Diana Bautista, professor of molecular and cell biology at UC Berkeley, member of the Helen Wills Neuroscience Institute, and a Howard Hughes Medical Institute (HHMI) investigator, the research demonstrates that specific SARS-CoV-2 enzymes directly stimulate airway sensory neurons, triggering immediate sneezing, coughing, airway inflammation, and heightened pain sensitivity.
How Viral Proteases Trigger the “Wasabi Receptor”
When SARS-CoV-2 infects host cells, it manufactures two specialized enzymes, papain-like protease (PLpro) and main protease (Mpro), to slice long viral polyproteins into functional components needed for viral replication. Once the virus kills the host cell, these viral proteases spill into the surrounding airway tissue, coming into direct contact with specialized pain- and irritant-sensing neurons known as nociceptors.
Bautista, who previously discovered that the TRPA1 ion channel acts as the sensory receptor for pungent chemicals in wasabi and garlic, found that SARS-CoV-2 hijacks this exact molecular pathway:
- Enzymatic Activation of TRPA1: Purified PLpro acts directly on the surface of sensory neurons to activate TRPA1 ion channels, prompting the release of neuropeptides that drive pain, airway hyper-reactivity, and autonomic reflexes.
- Catalytic Dependency: When researchers mutated PLpro to eliminate its enzymatic cutting ability, the protein lost its power to stimulate neurons, proving that its catalytic protease activity is required to trigger the neural response.
- Conserved Across Coronaviruses: PLpro proteins derived from SARS-CoV-1 and MERS-CoV similarly activated cultured sensory neurons, while Mpro triggered distinct neuronal reactions of its own.
Proving That Mice Sneeze
To test how PLpro behaves in a living organism, Bautista’s team applied just two microliters of purified PLpro to the nostrils of mice. While plain water occasionally elicited a single sneeze, PLpro triggered explosive bouts of up to 30 sneezes per minute, alongside heightened mechanical pain sensitivity.
Convincing peer reviewers that mice genuinely sneeze required rigorous physiological proof. The team acquired a specialized $75,000 plethysmograph to record the characteristic respiratory lung spasms accompanying each sneeze, matching patterns documented in other sneezing mammals, and dyed the nasal fluid blue to measure the expelled aerosol volume.
New Avenues for Acute Symptoms and Long COVID
While antiviral medications like Paxlovid target Mpro to halt viral replication, numerous experimental inhibitors targeting PLpro were developed during the pandemic without yet reaching clinical approval.
“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 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.”
Furthermore, direct viral sensitization of nociceptors offers a compelling biological mechanism for chronic neurological and respiratory complaints in long COVID—including persistent cough, shortness of breath, chest pain, and headaches.
“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,” Bautista noted. “So far, it looks like they can drive symptoms through both the immune system and the nervous system, using different molecular mechanisms.”
Questions and Answers
How does SARS-CoV-2 cause sneezing, coughing, and body aches so quickly?
Researchers discovered that when virus-infected cells die, they release viral enzymes, specifically papain-like protease (PLpro) and main protease (Mpro), that directly stimulate pain-sensing nerves (nociceptors) in the airways, triggering immediate sneezing, coughing, and pain rather than waiting solely for immune inflammation.
What is the TRPA1 receptor, and what does it have to do with COVID-19?
TRPA1 is an ion channel on sensory nerves famously known as the “wasabi receptor” because it detects irritating chemicals in wasabi and garlic. The study found that SARS-CoV-2’s PLpro enzyme directly activates TRPA1 on airway nerves, causing the release of neuropeptides that trigger coughing, sneezing, and pain.
Could these findings lead to new treatments for COVID-19 or long COVID?
Yes. Blocking the PLpro enzyme with targeted protease inhibitors could calm overactive sensory nerves, helping to stop severe coughing, reduce airborne viral spread, and potentially alleviate chronic neuropathic symptoms like persistent cough, chest pain, and headaches seen in long COVID.
Funding: The work was funded by grants from the National Institutes of Health (OD TR01 NS116992) and the Howard Hughes Medical Institute. Co-authors of the paper are Sonali Mali, Ricardo Silva, Zhongyan Gong, Michael Cronce, Uyen Vo, Cliff Vuong and Jeffery Cox of UC Berkeley and Yalda Moayedi of the New York University College of Dentistry. Bautista is a member of Berkeley’s Helen Wills Neuroscience Institute.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this autism Research:
- Media Contact: Robert Sanders
- Source: University of California – Berkeley
- Image Credit: Image credited to Neuroscience News
- Original Research is Open Access: Neuron (Nov 12, 2026). “A coronavirus protease activates sensory neurons via TRPA1 to drive sneeze, cough, and pain.” Authors: Sonali S. Mali, Zhongyan Gong, Ricardo Silva, Alexander N. Flamm, Christopher P. Cook, Lillian Shallow, Jennyffer Souza, Michael Cronce, Christopher J. Arp, Amr A.K. Mousa, Uyen Vo, Cliff Vuong, Jay Keasling, Yalda Moayedi, Jeffery S. Cox, Rithwik Ramachandran, Sarah A. Stanley, and Diana M. Bautista.
- DOI: 10.1016/j.neuron.2026.10.017
Abstract
A coronavirus protease activates sensory neurons via TRPA1 to drive sneeze, cough, and pain
Sneezing, coughing, and pain are common symptoms of respiratory viral infection. These responses are initiated by airway-innervating nociceptors that detect noxious stimuli, but how SARS-CoV-2 activates these neurons remains unclear.
Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating nociceptors in mice and human induced pluripotent stem cell (iPSC)-derived nociceptors. PLpro triggers sneezing, coughing, acute pain, and calcitonin gene-related peptide (CGRP) release in the airways.
Both the proteolytic activity of PLpro and the host ion channel transient receptor potential ankyrin 1 (TRPA1) are required for neuronal activation and sneezing. Infection with the mouse-adapted SARS-CoV-2 or the murine coronavirus MHV-A59 also induces sneezing in mice, and MHV-A59-evoked sneezing is TRPA1-dependent. SARS-CoV-2 infection of the trigeminal ganglia altered transcriptional programs associated with nociception, including upregulation of the TRPA1-CGRP signaling pathway activated by PLpro.
Together, these findings reveal a direct mechanism by which SARS-CoV-2 triggers pain and airway reflexes and identify PLpro and TRPA1 as potential therapeutic targets for COVID-19.
