Researchers at the University of California, Riverside, backed by a substantial NIH grant, are pioneering a study on the unique immune responses to obesity and parasitic infections, highlighting differences between males and females.
By exploring the interactions between specific immune cells and proteins like RELMalpha, they aim to unveil new pathways to treat these pervasive health issues.
Exploring Obesity and Helminth Infections
Scientists at the University of California, Riverside, have secured a $3.7 million grant from the National Institutes of Health (NIH) to explore how sex-specific immune responses influence obesity and parasitic worm infections — two major global health challenges.
Obesity affects more than two in five American adults, according to the Centers for Disease Control and Prevention (CDC). This widespread and costly condition is linked to serious health issues, such as type 2 diabetes and inflammatory disorders, and plays a key role in weakening the immune system.
Parasitic worm infections, also called helminth infections, occur when worms — known as helminths — enter the body. These infections can lead to various health problems, including anemia, pneumonia, malnutrition, abdominal pain, and diarrhea.
Investigating Sex-Specific Immune Responses
Led by Meera G. Nair, a professor of biomedical sciences at 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.
Immune System’s Role in Disease Combat
“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 at the UCR medical school. The multidisciplinary project involves aspects of endocrinology — hormones and sex differences — as well as computational biology and immunology.
Targeting Disease Mechanisms and Disparities
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.”
Focused Objectives in Sex-Specific Research
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.”
Computational Tools to Advance Research
Godzik, in charge of computational modeling, 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.”
Toward New Therapeutic Approaches
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.
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