Immune system proteins involved in severe parasitic disease identified

New insights into the mechanisms that cause more severe cases of schistosomiasis—a disease caused by parasitic worms and second only to malaria in terms of potential harm—have been revealed by researchers at Penn State.

The study, published in PLOS Pathogens, used a mouse model to examine how the body reacts to the parasite’s eggs, which trigger an immune response if they make their way into tissues and organs.

The researchers found that the activation of NLRP3 and AIM2 inflammasomes—proteins in immune cells that detect threats and trigger a response—is a key factor in severe inflammatory responses to these eggs.

“While the findings are preliminary, they provide a better understanding of how the body responds to the parasite and could help identify potential targets for developing future therapies,” said Parisa Kalantari, assistant professor of immunology in the College of Agricultural Sciences and lead author on the study.

The vast majority of known schistosomiasis cases occur in Africa, according to the World Health Organization, and people usually become infected after coming in contact with water infested with parasitic worm larvae.

While several species of blood fluke worms can cause schistosomiasis, the current study focused on Schistosoma mansoni. This species causes the intestinal and hepatic form of the disease, which results in various gastrointestinal symptoms. However, more severe cases can also result in liver fibrosis, portal hypertension, gastrointestinal hemorrhage or death.

Because schistosomiasis is considered a neglected tropical disease—described by the National Institutes of Health as diseases generally affecting people in poorer areas that have historically not received as much attention as other diseases—Kalantari said it’s important to find new treatments.

“The drug praziquantel continues to be effective against schistosome worms, but it does not prevent reinfection,” she said. “And while several vaccine candidates have been tested, none have shown consistent and acceptable high levels of protection. Therefore, it’s vital to develop new therapeutic approaches, especially when faced with high reinfection rates and the threat of drug resistance.”

For the study, the researchers first stimulated a type of immune cell called dendritic cells that were derived from mice infected with live schistosome eggs. Then, they measured the cytokines, or proteins that pass signals between cells, secreted from the dendritic cells, as well as levels of RNA and proteins from certain genes.

In a second set of experiments, the researchers examined mice infected with the Schistosoma mansoni parasite. Seven weeks postinfection, they evaluated inflammatory markers, liver granuloma size and main immune cell recruitment to the liver.

In addition to finding the inflammasomes associated with more severe disease, the researchers also found that caspase-1 and caspase-8 were key in activating these inflammasomes. These enzymes also helped activate another protein, Gasdermin D, which in turn facilitates the release of a proinflammatory cytokine. Additionally, the researchers found that mice deficient in Gasdermin D experienced less severe disease than control mice.

The researchers said it’s currently unknown which components of the schistosome actually activate the NLRP3 and AIM2 inflammasomes, and future research can focus on understanding these specific components.