Elucidating the mechanisms of sex-specific differences in the immune response to Strongyloides ratti infection

• Applicant: Professorin Dr. Minka Breloer
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555161012

The immune system's defense against infections is shaped by various factors such as age, genetic equipment, co-morbidities and lifestyle. In the last decade, sex or gender has come into focus as a highly relevant factor. Epidemiological data show that women are generally less susceptible to infections with virus, bacteria, protist parasites, and helminths, than men. Helminths still infect every 4th human, predominantly in the global south. Infections severely impair the quality of life as well as learning and working performance. Around 600 million people worldwide suffer from Strongyloides stercoralis infection, a soil transmitted parasitic nematode with tissue migrating and intestinal life stages. Following the general trend, the S. stercoralis infection incidence is higher in men compared to women. Of note, this difference may reflect biological sex-specific differences in the immune response and/or gender-associated social roles that impact exposition to infectious agents and health seeking behaviour. We use Strongyloides ratti-infected mice to study the protective immune response to helminth parasites and the immune evasive pathways, triggered by the helminth to survive despite being fully exposed to the immune system. Repeating early studies, we recorded elevated S. ratti burden in male mice compared to female mice, thus excluding gender-mediated effects that are absent in the mouse system. We hypothesize that Strongyloides infection triggers different immune responses in male and female mice that cause a female advantage in host defense. This proposal aims at elucidating the underlying immunological mechanisms. Sex differences in immunity can be caused by sex chromosomes and sex steroid hormones. As we and others show that castration of male mice reduced S. ratti parasite burden, we further hypothesize that these differences are partially hormone driven. Taking advantage of our groups 15-year experience in Strongyloides immunology, we intend to perform a comprehensive comparison of the immune response and immune regulation of S. ratti-infected male and female mice in vivo, to define the immunological defense mechanism(s) causing the female advantage. Using gonadectomy and sex hormone supplementation, we will define the responsible sex hormones and compare the function of male and female immune cells relevant for anti-S. ratti immunity in vitro in the presence of these sex hormones. Finally, using cell-depletion strategies we will provide causality between the immunological pathways modulated by sex hormones and the sex difference in susceptibility to S. ratti infection. In summary, we expect to gain in depth understanding of the differences in male and female helminth immunology, that have been neglected so far. This basic research-driven knowledge will ultimately contribute to a more specific treatment of helminth-induced diseases taking into account biological sex as a still understudied but highly relevant variable.

• DFG Programme: Research Grants