Pitt study uncovers how the immune system fends off gut parasites

(Press-News.org) New research from the University of Pittsburgh reveals how the immune system defends against intestinal parasitic worms, or helminths, one of the most common infections worldwide in communities with limited access to clean water and sanitation.

The findings, published today in the journal Immunity, suggest that currently available non-steroidal anti-inflammatory drugs (NSAIDS), similar to ibuprofen, could act on the newly discovered pathway to boost immunity to parasitic infections.

“While parasitic worms are less of an issue in most of the U.S. and other wealthy nations, these infections affect almost a quarter of the world’s population,” said co-senior author Reinhard Hinterleitner, Ph.D., assistant professor in the Pitt Department of Immunology. “But there hasn’t been a new medication developed to treat parasites for decades, so there is a huge need for novel treatments. While more research is needed, our study suggests that existing medications could be repurposed to treat parasitic infections.”

There are several different types of immune responses, according to co-senior author Yi-Nan Gong, Ph.D., assistant professor in the Pitt Department of Immunology and member of the Tumor Microenvironment Center at UPMC Hillman Cancer Center. The more familiar type 1 immunity combats viruses and bacteria by directly annihilating these pathogens, while type 2 is a broader defense against external threats such as parasites. Erroneous activation of type 2 responses is also associated with food and environmental allergies.

“Type 2 immunity is like an eviction campaign,” said Gong. “By driving inflammation and accelerating cell turnover and differentiation, it makes the gut environment inhospitable for parasites, naturally expelling them.”

To learn more about type 2 immunity in response to helminth parasites, Hinterleitner and Gong looked at a protein called Gasdermin C, which is found at low levels in the healthy gut and increases in response to parasitic infection. Gasdermins are inactive until they are chopped in half by an enzyme called a protease, which releases an active protein fragment.

The researchers discovered that a protease called Cathepsin S activates Gasdermin C in both mice and humans. Wiping out either Gasdermin C or the protease impaired type 2 responses to helminth infections in mice, showing that both are essential for immunity to parasites.

Once activated, most gasdermins act to trigger cell death, which eliminates infected cells and releases signals that recruit immune cells. Hinterleitner and Gong were surprised to find that Gasdermin C worked differently: The active fragment of Gasdermin C targets and penetrates Rab7-positive vesicles — a type of structure that transports cellular materials — leading to a reduction of a chemical messenger called prostaglandin d2.

Because prostaglandin d2 dampens type 2 responses, by reducing levels of this chemical messenger, Gasdermin C boosts immunity and clears intestinal parasitic infections.

“This finding offers new perspectives for anti-parasitic therapies,” explained Gong. “One promising approach involves cyclooxygenase (COX) inhibitors. Prostaglandin d2 synthesis depends on COX. Common COX inhibitors, including NSAIDs like ibuprofen, are widely used and safe for both adults and children.”

The researchers emphasized that clinical trials are needed to confirm the effectiveness of this approach in humans and cautioned that people should consult their provider before taking any new medications.

The study also showed that certain microorganisms called commensal gut microbes — residents of the intestine that are typically harmless — can trigger type 2 immunity in mice. This finding suggests that, under specific disease conditions such as food allergies and inflammatory bowel disease (IBD), commensal microbes may contribute to symptoms driven by type 2 immune responses.

“The gut microbiome plays an important role in the development of food allergies and IBD,” said Hinterleitner. “It is possible that, with further study, identifying microbes that induce Gasdermin C could be used as a marker or predictor of the risk of food allergies.”

Other authors are listed in the manuscript.

This research was supported by the Department of Immunology Investigator Start-up Fund, the National Institutes of Health (R21AI163721, R01AI168478, P30CA047904, DP2GM146320, R01DK130897, R01CA293654, T32AI089443 and F31 DK138621), the Austrian Marshall Plan Foundation, the American Association of Immunologists Intersect Fellowship, the Tsinghua University and China Scholarship Council fellowship and the National Key R&D Program of China (2021YFA1101002, 2021YFA1300302).

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