Probing connections between obesity and parasitic worms

Biomedical scientists at the University of California, Riverside have received a $3.7 million grant from the National Institutes of Health to study the role of sex-specific immune responses in obesity and parasitic worm infections - both significant global public health concerns.

According to the Centers for Disease Control and Prevention, more than two in five American adults have obesity, a common and costly chronic disease. Linked to chronic conditions like type 2 diabetes and inflammatory disorders, obesity has been identified as a critical factor in immune system dysfunction.

A parasitic worm infection, also known as a helminth infection, occurs when parasitic worms, or helminths, infect the body. Helminth infections can cause several health issues, including anemia, pneumonia, malnutrition, abdominal pain, and diarrhea.

Meera Nair is the principal investigator of the NIH grant.

Led by Meera G. Nair, a professor of biomedical sciences in the UCR School of Medicine, the researchers will use a mouse model to focus on the role of macrophage-eosinophil interactions in the progression of these diseases. A particular focus will be the RELMalpha protein, which is released by macrophages in a sex-dependent manner.

Macrophages and eosinophils are types of disease-fighting white blood cells. RELM, or resistin-like molecules, are proteins that are highly expressed in infectious and inflammatory diseases. One of these proteins in mice, RELMalpha, regulates the function of macrophages and eosinophils, and shares expression patterns with resistin in humans.

"Macrophage-eosinophil interactions are crucial for the immune system's ability to combat obesity and helminth infections," said Nair, the five-year grant's principal investigator. "We are proposing that macrophages and eosinophils driven by helminth infection may help protect against obesity differently in males and females."

Nair will be joined in the research by co-investigators Adam Godzik and Djurdjica Coss, both professors of biomedical sciences in the UCR medical school. The multidisciplinary project involves aspects of endocrinology - hormones and sex differences - as well as computational biology and immunology.

The team has already begun to explore how differences in immune responses between males and females may influence the outcomes of both diet-induced obesity and parasitic helminth infections, which together affect over two billion people worldwide.

"We would like to understand the underlying immune mechanisms that contribute to the disparities we see in obesity and parasitic infections," Nair said. "By understanding how sex-specific immune responses affect disease outcomes, we hope to develop new, more effective treatments for both metabolic disorders and helminth infections."

The team has found that parasitic worm infections turn on eosinophils and the protective immune response, suggesting that understanding the protective pathways involved could mitigate diseases.

"We would like to fully understand what regulates and turns on these eosinophils, particularly in adipose or fatty tissue," Nair said. "Our preliminary work shows that RELMalpha is a very good candidate. Our mouse models show its response depends on whether the mouse is male or female. We are now looking at the underlying sex differences and how endocrine controls can be different in males versus females. Ultimately, we want to find the best protective pathway against metabolic dysfunction."

The research has three main objectives, spearheaded by Nair, Coss, and Godzik, respectively:

• Determining how RELMalpha influences macrophage differentiation and eosinophil responses within the adipose (fat) tissue microenvironment, with a focus on sex-specific mechanisms.
• Examining how macrophages and eosinophils function differently in males and females and their potential role in defending against obesity and helminth infections.
• Combining lab-derived single cell sequencing data with publicly available datasets to identify specific eosinophil subpopulations and the cellular pathways involved in type 2 immunity.

Coss explained that her contribution to the project will be understanding how different sexes respond to obesity.

"Research has shown that there are significant sex differences in the immune system and inflammatory diseases such as obesity and helminth infection," she said. "Results from our project will help us understand the basic science about these differences and suggest possible approaches that can be applied in the clinic."

Godzik, in charge of computational modelling, is developing a website for sharing datasets and software related to the research that will be made publicly available.

"We have considerable experience in not only developing computational tools but also providing the scientific community with access to them," he said. "The new tools we are developing for this project will be specific to the unique population of eosinophils. People can download and use them. People can also upload their own data for analysis by our software."

According to Nair, understanding the role of the immune system in obesity and metabolic disease is more urgent than ever. She said the complexity of the immune system in obesity and metabolic diseases, especially as it relates to sex-specific and hormonal differences, is an underexplored area.

"What sets our research apart is its focus on the sex-specific immune mechanisms at play," she added. "It's rare to have an infectious disease immunologist, an endocrinologist, and a computational modeler with background in medicine to be able to address this topic. We hope to take advantage of our unique collaboration to arrive at insights leading to new therapeutic approaches for managing obesity and related diseases, particularly in men who are disproportionately affected by these diseases."

The research team will include two postdoctoral researchers and two graduate students.

Header image shows, from L to R, Meera Nair, Djurdjica Coss, and Adam Godzik.

Share this Article

Health