Gut bacteria blocks and enhances virus

Illustration of electron microscopic imagery of a number of norovirus virions.
This illustration is based upon electron microscopic imagery and provides a three-dimensional, graphical representation of a number of norovirus virions; illustration credit: Alissa Eckert, MS. Used under a creative commons license agreed to by the CDC Public Health Image Library.

As temperatures cool, relief from summer heat is replaced for the unlucky with winter’s queasy bane: norovirus. 

The virus spreads easily and causes vomiting and diarrhea. Ingestion of merely a few viral particles produces illness, and unfortunately catching it provides only short-lived protective immunity. 

Stephanie Karst, Ph.D., a professor of molecular genetics and microbiology in UF’s College of Medicine, recently discovered that bacteria present in different regions of the gastrointestinal tract of mice either enhance or block murine norovirus.

Karst’s interest in the virus stretches back to 2003 when she was on the team that first discovered murine norovirus. She is also affiliated with the Emerging Pathogens Institute. 

Prior studies have demonstrated that the amount of infectious virus produced in antibiotic-treated mice infected with other intestinal viruses, such as poliovirus and rotavirus, is lower compared to those with intact microbiomes. This indicated that commensal gut bacteria somehow enhanced infection of these intestinal viruses. 

Karst wondered if the same processes would hold true for murine norovirus, or MNV, so she and a team of researchers tested how antibiotic-treated mice would respond to MNV infection in 2014. Her team found that the bacteria which occur naturally in the GI tracts of mice also enhanced MNV infection.

Karst was continuing to investigate exactly how gut bacteria might facilitate MNV infection when her team was surprised to discover that bacteria present in specific sections of a mouse’s GI tract blocked infection while bacteria in other sections enhanced it. 

These latest results were recently published in Nature Microbiology; Karst was the senior and co-corresponding author to the study, along with Megan Baldridge, M.D., Ph.D., an assistant professor at Washington University’s School of Medicine. Additional coauthors from UF’s College of Medicine, department of molecular genetics and microbiology include: Katrina Grau, Shu Zhu, Emily Helm, Drake Philip, Matthew Phillips and Abel Hernandez. All the authors also share EPI affiliations.

The research team measured virus titers at three different places along the small intestine (SI-1, SI-2 and SI-3, in descending order from the stomach), as well as in the cecum and the colon. They were expecting to find that gut bacteria increased MNV infectivity on the whole. But instead, they found reduced titers in the regions closer to the stomach, which indicates something acting to block MNV infection. And they found increased titers in the distal region, which indicates that something aided infection in this region. 

In a normal scenario, Karst says, gut bacteria activate tolerogenic signals; these are communications that instruct the immune system to tolerate specific microorganisms. “We have trillions of bacteria in our guts,” Karst says. “Normally these commensal bacteria will drive an immune-tolerant response, and that benefits the host. Because if we responded to all of these bacteria, that would not be conducive to health because your gut would constantly be inflamed.”

But the presence of a viral pathogen should override this tolerogenic signal and produce an immune response. “In the distal gut, we think the virus has evolved to use these commensal bacteria to its own advantage,” Karst says. “There, the bacteria are really helping the virus, which is why you see increased titers in this region. You can have an immune response at one site within the gut that may not be conveyed across the length of the GI tract, because the tissues are functionally compartmentalized.” 

Although establishing the mechanism at work was beyond the scope of her current paper, her team proposed a possible process. In the proximal gut, they believe that bile acids activate signaling proteins, called interferons, which switch on an immune response to fight pathogenic invaders. But in the distal gut, these bacterial metabolites fail to activate interferons possibly because of dominant tolerogenic signals.

Essentially, the immune system misses recognizing the virus in the distal gut and it is then free to wreak havoc.

While MNV differs in some ways from human norovirus, Karst says basic research such as this can eventually help develop drug therapies. 

“Anytime we can uncover how the immune system blocks a specific type of infection, we can build on that for designing anti-virals,” Karst says. 

And wouldn’t the best Holiday gift of all be to banish winter’s queasy bane? 

By: DeLene Beeland