By: Pooja Sharma

Norovirus, also known as winter vomiting bug and cruise ship virus, is one of the most common causes of viral gastroenteritis in humans. It is an extremely contagious virus and as few as 20 virus particles are enough to cause an infection. Its contagiousness is the reason why it is most common in communal facilities, such as: cruise ships, camps, prison, school, hospitals, dormitories, etc. Norovirus is responsible for 90% of all the epidemic non-bacterial outbreaks of gastroenteritis in the world and is the culprit behind about 50% of all the foodborne outbreaks that occur in the United States.

Immunity published a new study in which researchers from Perelman School of Medicine at the University of Pennsylvania used a mouse model to demonstrate that, even in immunized animals, noroviruses can escape the immune system and still be spread by hiding out in an extremely rare type of gut cell.

Senior author of the study – E. John Wherry, PhD, Professor of Microbiology and Director of the Penn Institute of Immunology mentioned that current vaccines for Norovirus have been ineffective even after strong antibody response. He further added, “Creating an understanding behind the unique norovirus characteristic of hiding from the host immune system may explain the biology and present opportunities to improve vaccines and therapeutics.”

There are a few people who shed out the complete virus within a few days while there are some who keeps shedding out the virus, a few weeks and months after becoming infected. These individuals who persistently carry the virus are a major source of the outbreaks and epidemics. But, it was still unclear why their immune system failed to eliminate the virus just like others.

“The cruise ships outbreak of Norovirus are high profile, but it happens everywhere from daycare centers, eldercare facilities and more,” said the first author Vesselin T.Tomov, MD, PhD, an assistant professor of gastroenterology. “Norovirus can cause persistent infections, challenging the long held view that they are transient pathogens.”

THE EXPERIMENT:

The researchers at University of Pennsylvania worked on the T-cell responses in mice infected with either acute or chronic strain of mouse norovirus by defining and tracking them. It will help to gain insight into mechanisms that are involved in viral clearance and viral persistence. At first, the scientists hypothesized that persistent norovirus infection could lead to T cells becoming exhausted and this, rendering them non-functional just like what happens with HIV or Hepatitis C. But they were surprised to see that T cells remained functional even after months of norovirus infection.

The team then, looked into the earliest stages of response by the immune system and found 2 phases to that response. During the beginning stages of the responses, T cell reacted strongly to the virus and controlled it. But, after around 3 days of the infection, the T cells could no longer detect the norovirus in 50-70% of the mice infected by the chronic strain.

The researchers faced an anomaly because the T cells who were supposed to react to the virus seemed ‘unable to see’ or ‘ignorant’ towards the virus. And yet, there was a persistent shedding of norovirus in the feces of the infected mouse. To explain this riddle, they next hypothesized that these actively multiplying norovirus are cloistering somewhere in the gut, which is out of reach of the T cells.

CONCLUSION:

Tomov, then conducted a series of experiments to test the hypothesis. He eventually did get to the result that Norovirus hides in rare gut cells which can make it difficult to detect by the T cells and hence, alert them for the presence of a pathogen. “We found a novel escape mechanism where norovirus becomes essentially invisible to the immune system while still producing large amounts of virus that gets shed from the intestine,” said Tomov.

Coauthors at Washington University found that Norovirus find its refuge in specialized, ultra-rare cells of the gut lining, which is in order of only a few hundred cells out of billions that line the mouse gut. These cells are the primary factories of Norovirus production and allows the virus to evade the immune system without getting detected.

These findings also explain so as to why the vaccines of Norovirus that are being tested shows limited effectiveness. It also gives a hint that future vaccines would need to give elicit immunity that acts quite robustly during the first 3 days before the virus moves into hiding. The result also coincides with the fact that no one has yet found any animal reservoir of the virus. And to add to all this, there may exist some individuals who are living with this long standing strain of the virus and are continuously, yet unknowingly shredding it.

With this new findings in mind, researchers are now investigating on how to improve protection against this virus by blending in the T cell and antibody approaches for vaccines. When you identify the cellular reservoir of Norovirus, there is a new hope in the development of therapeutics that can help prevent or purge any persisting infection. In addition to that, testing on whether similar mechanisms occur in the humans is a major finding that would not only help move forward the vaccine development but will also help in testing the potential role of Norovirus as a cofactor in other gastrointestinal diseases.

Norovirus is an expensive and serious health issue especially among children, elder people and those with weakened immune system. The symptoms of the virus include diarrhea, nausea, vomiting, abdominal pain and low grade fever. Most people recover within 2-3 days and severe illness is rare. Most Norovirus outbreaks are traced to food that is handled by just one infected person. Shellfish and salad ingredients are most likely to be implicated in the Norovirus outbreaks.

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