Genetic determinants of host immunity-mediated resistance to helminth infection

About This Grant

PROJECT SUMMARY Helminth infections are a major public health concern affecting over 1.5 billion people worldwide. Type 2 immune responses, marked by strong production of signature cytokines IL-4, IL-5, and IL-13, are the hallmarks of helminth immunopathogenesis. While it has been shown that human genetic variations contribute to the heterogeneity of Type 2-associated immunity, the genetic determinants predisposing individuals to become more susceptible/resistant to helminth infections remain unknown. Ascaris sp., the most prevalent helminth parasite globally, has a life cycle involving transient larval migration through lung tissue and airways, leading to a pulmonary eosinophil-rich Type 2 inflammatory response. The well-studied murine model of Ascaris infection replicates the human biological process, providing a valuable tool to study tissue-specific immune responses and host susceptibility, which are challenging to investigate in human populations. This project leverages the high genetic variability of a large panel of recombinant Collaborative Cross (CC) mice to uncover novel genetic determinants of host immune responses during Ascaris infection. We hypothesize that host immunity to Ascaris is genetically determined, with genetic differences driving distinct immunological responses that affect the progression of the infection. By integrating phenotypic screening with advanced genetic mapping techniques, we aim to identify and validate key genes that modulate host-parasite interactions during the lung stage of infection. Preliminary studies using eight genetically distinct Collaborative Cross (CC) founder strains, A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ, we showed that host immunity to Ascaris is genetically determined. Our data revealed significant variability in parasite burden and lung inflammation phenotypes, notably a unique SiglecF+ eosinophilic response in the resistant CAST/EiJ strain. In this study we take an innovative approach of combining phenotypic screening of parasite burden and its associated immunopathology in the lung with advanced genetic mapping techniques, using a large panel of 50 fully sequenced CC mouse strains. The outcomes of the following AIMS will represent the significant reward of mapping not only the genetic loci of the host protective immunity against Ascaris parasites, but also identifying key genes involved in the development of Ascaris-induced pulmonary eosinophil-dominated inflammatory response in the lungs (Loeffler syndrome), filling a significant knowledge gap. Using quantitative trait locus (QTL) mapping, we aim to identify loci associated with pulmonary inflammation-mediated parasite resistance. This study seeks to advance our understanding of the genetic basis of a protective immunity to helminth infections, ultimately contributing to improved prevention and treatment strategies.