COVID-19 News: Scientists From University Of California Unravel As To How SARS-CoV-2 PLpro Protein Makes One To Sneeze!

COVID-19 News: As the global fight against the COVID-19 pandemic continues, scientists at the University of California have unearthed a new facet of the SARS-CoV-2 virus - its ability to induce sneezing. Beyond the well-known severe respiratory symptoms, this breakthrough covered in this COVID-19 News report reveals a deeper understanding of the virus's mechanisms. The discovery of a specific viral protein, PLpro, responsible for stimulating neurons in respiratory passages and triggering the sneeze reflex, not only sheds light on a previously unknown symptom but also opens up new possibilities for treatment and transmission reduction.


How SARS-CoV-2 Causes One To Sneeze
 
The Sneezing Mechanism
Traditionally considered an incidental byproduct of illness, sneezing has been assumed to result from infected cells releasing molecules that irritate nasal passages. However, neurophysiologist Dr Diana Bautista and her team at the University of California, Berkeley, suspected a more direct role for SARS-CoV-2 in this reflex. Their groundbreaking study demonstrated that the viral protein PLpro, produced in significant amounts by infected cells, directly activates a subset of sensory neurons called nociceptors, responsible for inducing sneezing.
 
Upon introducing PLpro into the noses of mice, the researchers observed a rapid and robust sneezing response. This not only affirmed a direct connection between the viral protein and the sneeze reflex but also raised questions about its potential role in promoting virus transmission. The study's findings indicated that PLpro stimulates calcium influx in nociceptors, triggering the release of large quantities of nasal secretions, providing a potential mechanism for the spread of the virus.
 
Beyond Sneezing: Implications for COVID-19 Symptoms
While sneezing is a crucial element of the body's defense against harmful substances, Bautista's study delved further into PLpro's impact on other symptoms associated with COVID-19. Mice injected with PLpro displayed face and mouth pain, common in COVID-19 patients. Additionally, the researchers implicated PLpro in nocifensive behaviors, such as nose rubbing, further highlighting the protein's role in inducing irritation and pain.
 
Furthermore, the researchers tested two other coronaviruses, finding that PLpro from the severe acute respiratory syndrome (SARS) virus also stimulates sensory neurons. This suggests that the phenomenon of PLpro-triggered sneezing may extend beyond SARS-CoV-2 to other coronaviruses and even viruses causing common colds.
 
Challenges and Considerations
Despite the promising findings, caution is warranted. Neuroimmunologist Dr Felipe Ribeiro from Washington University School of Medicine in St. Louis urges researchers to rule out the possibility that sneezing might have a beneficial role in the recovery from COVID-19. Blocking the sneezing reflex needs to be demonstrated as safe and not detrimental to the overall healing process.
 
The Vira l Protease PLpro: A Common Thread Among Coronaviruses
The study also explored the broader implications of PLpro, highlighting its presence in other coronaviruses like SARS and Middle East respiratory syndrome (MERS). While the sequence similarity is significant among these viral proteases, variations in structure and catalytic efficiency were noted. This raises intriguing questions about whether PLpro from other viruses, including those causing the common cold, might also actively trigger sneezing and pain.
 
Unraveling the Molecular Mechanisms: PLpro and Sensory Neurons
The research delves into the molecular intricacies of how PLpro activates sensory neurons. The protein, released at nanomolar concentrations from infected airway epithelial cells, stimulates a subset of airway-innervating nociceptors, which express the ion channels TRPV1 and TRPA1. This activation prompts rapid and robust calcium transients, inducing behaviors such as sneezing, nose rubbing, and orofacial pain.
 
A Novel Role for PLpro in Long COVID
As scientists strive to comprehend the lingering effects of COVID-19, the study suggests a potential link between PLpro and Long COVID. Over 10% of SARS-CoV-2 patients experience chronic symptoms, including headache and peripheral neuropathy. The research indicates that PLpro, even in the absence of active infection, may persist in the body, contributing to long-lasting changes in sensory neurons and potentially influencing chronic symptoms.
 
Implications for Long COVID
As more than 10% of SARS-CoV-2 patients experience chronic symptoms well after the acute infection phase, known as Long COVID, scientists are investigating the potential connection between PLpro and these lingering effects. The most prevalent Long COVID symptoms include headache, shortness of breath, persistent cough, sore throat, and chest pain. Peripheral neuropathy symptoms, such as pins and needles and numbness, have also been reported more frequently than in control groups.
 
A hallmark of neuropathic diseases, including chronic pain and itch, is transcriptional changes in sensory ganglia that drive aberrant neuronal activity. Long-term alterations in nociceptor function are critical to understanding the mechanisms behind Long COVID. Future studies are needed to assess whether infection-induced gene expression changes persist beyond infection and whether PLpro, like other viral proteins, lingers in the body after active infection, contributing to Long COVID symptoms.
 
Potential Therapeutic Targets
The significance of PLpro in both SARS-CoV-2 infection and symptom manifestation makes it a potential therapeutic target. Since PLpro is crucial for the virus's ability to infect cells, researchers are already exploring it as a drug target. Several compounds inhibiting PLpro are in preclinical development, raising the possibility that targeting this protein could not only hinder viral replication but also alleviate symptoms and reduce transmission.
 
Conclusion
The study findings unravels the mysteries behind how SARS-CoV-2 induces sneezing, shedding light on the virus's intricate mechanisms. The role of the viral protein PLpro in directly stimulating sensory neurons provides not only a deeper understanding of COVID-19 symptoms but also potential therapeutic avenues. As the scientific community continues to explore the complexities of the virus, targeting PLpro emerges as a promising strategy to alleviate symptoms, hinder transmission, and potentially address the enigma of Long COVID. The ongoing research into the interplay between PLpro and the human body offers hope for more effective treatments and a comprehensive understanding of the long-term effects of this unprecedented global health crisis.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2024.01.10.575114v1
 
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