Researchers have found that infection with parasitic helminth worms in the gut can act as a gateway for worsening infections from neuropathic viruses in mice by causing the natural microbiome in the gut to spread throughout the body, shifting the focus of the immune system away from the viral infection and ultimately making the mice more vulnerable to serious complications or death.

The study, published Feb. 25 in Cell, shows how a seemingly unrelated parasite can start an immune-response domino effect, provided the parasite and the virus are in the same place. Notably, the worms used in the study did not make the animals sick on their own.

"If you had a worm that made them sick, sick animals get sicker if you give them a second infection, generally speaking," said senior author Michael Diamond, a pathology and infectious diseases professor at Washington University School of Medicine. "But here, they're perfectly fine. They get an infection for a couple of weeks, and then they clear it, and then it's gone. So it's a transient infection."

However, for many cases in humans, intestinal worms are far from a transient infection. Helminth infections affect up to 2 billion people worldwide. They are particularly prevalent in the developing world and can cause symptoms such as diarrhea, abdominal pain, intestinal obstruction, anemia and stunted growth and cognitive development in children.

The researchers sought to discover how these gut parasites interact with flaviviruses, a large family of viruses of which 70 are known to cause human diseases. While it may not be the most obvious interaction to investigate, diseases caused by flaviviruses are similarly prevalent in the developing world because many of them are spread by mosquitoes, ticks or other arthropods. These diseases include Zika, dengue, yellow fever, tick-borne encephalitis and West Nile virus.

"Because some of the viruses that we work on are endemic in the developing world … we became interested in this question," Diamond said. "How do helminths, where people in the developing world may be infected with multiple helminths, how do they modulate infection for systemic viruses, both those that travel to the gut and those that don't travel to the gut?"

While many flaviviruses are not associated with specific gut illnesses, as opposed to other viruses like rotavirus or norovirus, Diamond explained that there is a growing scientific interest in exploring how the gut can contribute to systemic infections throughout the body.

To explore this relationship, the team infected mice with both a parasitic worm and West Nile virus, and compared the health outcomes with those of mice that were infected with just the worm.

What the team found is that having both infections at the same time caused significant damage to the lining of the gut, much more than either organism would have produced on its own. This damage resulted in a chain reaction where bacteria normally housed in the gut spread throughout the body, compromising the immune system of the mouse, then allowing West Nile virus to infect the brain, killing the mice.

"It killed them not necessarily because of what happened in the gut, but because once the worm/virus mix led to the compromised microbiome and the barrier compromising bacteria translocating, the T cell response was collapsed," Diamond said. "It actually went from a normal response down to almost no response, and then the virus disseminated in the brain and the spinal cord, and that's what killed the animals."

The team is next interested in exploring the effects of worm coinfection on viruses that affect other areas of the body, as well as extending the findings to larger animals. Diamond speculates that in the future, this mechanism may contribute to alternative treatments for severe flavivirus infections in developing countries by targeting parasitic worms.

"There's this question of, can we generalize and translate these findings to other worms, how does it work in other animals, and ultimately," Diamond asked, "Could we make an intervention based on anti-helminthic drugs to modulate the disease pathogenesis of these other viruses, which can cause severe clinical syndromes?"

The study, "Enteric helminth coinfection enhances host susceptibility to neurotropic flaviviruses via a tuft cell-IL-4 receptor signaling axis," published Feb. 25 in Cell, was authored by Pritesh Desai, Hana Janova, James P. White, Megan T. Baldridge, Larissa B. Thackray and Michael S. Diamond, Washington University School of Medicine; Glennys V. Reynoso and Heather D. Hickman, National Institute of Allergy and Infectious Diseases; Joseph F. Urban Jr., U.S. Department of Agriculture; and Thaddeus S. Stappenbeck, Cleveland Clinic.