Regulation of mucosal immune responses by helminth infections

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

Type 2 immune responses operate under varying conditions in distinct tissue environments and are crucial for protection against helminth infections and for the maintenance of tissue homeostasis, especially at mucosal tissue sites. We are utilizing technological advances in genomics to generate new insights into the cellular and molecular heterogeneity of type 2 immune responses to helminth infections. By using computational biology approaches to integrate complex multiparameter data, we are investigating how genetic and environmental heterogeneity contributes to the varying magnitude and quality of the type 2 immune response during infection. We have utilized a variety of mouse models and clinical and translational research studies to examine the effects of helminth infections on the gut microbiota and the intestinal immune response. Through our field studies in Malaysia and Colombia, we have calculated the relative effect sizes of diet, clinical lab parameters, blood transcriptional profiles and parasitic infection status on the gut microbiota communities. We have found that the effects of helminth infections on the gut microbiota could vary based on the field site, and in some situations are less impressive than infection with Plasmodium parasites. Recent data obtained from metagenomics and metatranscriptomics analysis of fecal samples collected in Malaysia indicate that a large number of bacterial taxa in this region are uncharacterized. Metagenomics data enables us to calculate replication of specific bacterial taxa that we find to be associated with helminth infections, as well as bacterial taxa where replication is inhibited by helminth presence. We have also been interested in how intestinal helminths may improve symptoms of inflammatory bowel disease patients by restoring the mucosal barrier. Recently, we used single-cell RNA-sequencing to examine lamina propria CD45+ hematopoietic cells from patients with inflammatory bowel disease (IBD), in collaboration with colleagues at NYU School of Medicine. We identified a population of IL-1b+Lyz+ antimicrobial macrophages and Foxp3+Batf+ T cells that are associated and expanded in inflamed tissues, which we further validated in other scRNA-seq datasets from IBD patients. We generated a cell type specific expression matrix to infer representation from bulk RNA seq datasets, which further implicated antimicrobial macrophages expressing IL-1B with S100A8/A9 calprotectin transcripts as being associated with inflammation, as well as being correlated with Bacteroides and Escherichia bacterial species. Finally, we find that Vedolizumab and Etrolizumab non-responsiveness in ulcerative colitis patients is associated with the signature of this antimicrobial macrophage population in a subset of patients. In addition to these clinical studies on human cohorts, we have collaborated with colleagues at Princeton University to examine the effects of rewilding mice on the immune response. The relative contributions of genetic and environmental factors to variation in immune responses are poorly understood. This system enables us to introduce mice with specific genetic makeups into a radically altered environment from the laboratory conditions. We performed a detailed phenotypic analysis of immunological parameters in after release into this outdoor enclosure. Interestingly, we find that variations of immune cell populations were largely driven by the environment, whereas cytokine production elicited by microbial antigens was more affected by the genetic mutations. Therefore, exposing laboratory mice with genetic mutations to a natural environment uncovers different contributions to variations in microbial responses and immune cell composition. Recently, we have further investigated several inbred strains of mice (129, PWK and C57BL/6) to examine the effects of a wider range of genetic variation, in combination with environment and infection (Trichuris muris) at determining immune variation. We believe that by better understanding the mechanisms underlying the heterogeneity of type 2 immune responses between individuals, we will be better able to treat any diseases in which type 2 immunity is an important component.