Viral protein activates the neurons in the respiratory tract; it may be a therapeutic target.
SARS-CoV-2 can make patients miserable in a number of ways, one of which is by having them sneeze. Researchers have now found the reason behind this snarky impact. The sneeze reflex is caused by a protein produced by the virus stimulating neurons in the respiratory passages. The findings may lead to the development of new therapies that lessen COVID-19 symptoms and stop SARS-CoV-2 from spreading.
They might also apply to other sneeze-inciting viruses. “Prior to this study, nothing was known about how viruses cause sneezing,” says neuroimmunologist Isaac Chiu of Harvard Medical School, who wasn’t connected to the research. The study is the first to show that a viral protein “can be directly sensed by neurons to cause sneezing.”
Sneezes have a preventive effect, clearing the body of irritating and sometimes dangerous chemicals. They also aid in the spread of infections like SARS-CoV-2 to new hosts. Up to eight meters can be covered by 40,000 virus-laden droplets propelled by a human sneeze. However, scientists surmised that sneezes are an unintentional consequence of disease, since diseased cells release chemicals that irritate nasal passages.
SARS-CoV-2 may have a more direct impact, according to neurophysiologist Diana Bautista of the University of California, Berkeley and her associates. The viral protein PLpro, which is a member of the protease family of enzymes that cleaves other proteins, is released in high quantities by infected cells. Other proteases produced by bacteria, plants, and even humans have been shown in earlier studies to activate sensory neurons, which are the cells responsible for sneezing.
When PLpro was injected into the mice’s noses, the researchers discovered that it activated nociceptors, a subset of sensory neurons that are responsible for pain and itching. Next, the group investigated how the protein affected sneeze. In contrast to 30 seconds after receiving a control mixture, the rats began sneezing approximately 14 seconds after being exposed to PLpro. In the first two minutes after receiving PLpro, mice sneezed about four times more frequently than controls, according to a preprint published on bioRxiv on January 11th.
“We were excited and horrified” by the results, Bautista says, because they show a powerful effect on sneezing that could promote virus transmission. By inserting blue dye into the animals’ noses along with the test solutions and measuring spatter on the floors of their cages, the team showed sneezes expelled large quantities of nasal secretions.
Because researchers are unsure whether mice actually cough, the team was unable to evaluate whether PLpro promotes coughing, another symptom of virus propagation, according to Bautista. However, her research did link PLpro to oral and facial pain, which is also common in COVID-19. The rats wiped their faces more frequently with their front paws after the protein was injected into their cheeks, indicating that they were in pain.
After testing two more coronaviruses, the scientists discovered that PLpro, the virus that causes severe acute respiratory syndrome, also activates sensory neurons. According to Bautista and colleagues, the protein is also carried by other viruses, including several that cause colds, and this suggests that these viruses may potentially actively produce sneezes.
PLpro does not directly act on protein channels; rather, it prompts the channels to open, thereby activating nociceptors by calcium entry. It appears to target a separate receptor that the researchers are still trying to figure out.
“What they’ve found is very compelling,” says neurobiologist Theodore Price of the University of Texas at Dallas. Because PLpro is necessary for SARS-CoV-2 to infect cells, researchers are already exploring it as a drug target. Dozens of compounds that might block the protein are in preclinical development. The new results suggest these candidates could also quell symptoms and hinder transmission. But neuroimmunologist Felipe Ribeiro of Washington University School of Medicine in St. Louis cautions that researchers must rule out the possibility that sneezing speeds recovery from COVID-19. “You have to show that blocking it is not harmful.”