Regulation of mucosal immune responses by helminth infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 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 immune response during infection. We have utilized a variety of mouse models and clinical and translational research studies to examine interactions of helminth infections with the microbiome and the immune response. Through our field studies in Malaysia, we have calculated the relative effect sizes of diet, clinical lab parameters, blood transcriptional profiles and parasitic infection status on the microbiome. Recent data obtained from metagenomics and metatranscriptomics analysis of samples collected in Malaysia indicate that a large number of bacterial taxa in this region are uncharacterized. Individuals from villages with higher prevalences of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition are strongly associated with urbanization and the effects of helminth infection status on the microbiome varies by village. Furthermore, a substantial quantity of the microbiome, including the virome, remains unannotated and this large dataset from an indigenous population associated with helminth infections is a valuable resource for future studies. We have now identified immunological parameters in the blood (cytokines and chemokines), which are associated with the relative abundances of some of the new bacterial communities. While addressing health concerns of the Orang Ali, in collaboration with Dr. Julie Segre and Dr. Heidi Kong, our studies have expanded beyond the gut microbiome to include the skin microbiome and its interaction with fungal infections. We characterized a rare fungal infection and provided evidence for the emergence of anti-fungal resistance genomically. We also examined the consequences of urbanization on the skin microbiome. We have also collaborated with colleagues at Princeton University to examine the effecs 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. We have now 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. Whereas cytokine response heterogeneity is driven primarily by genotype, cellular composition is driven by interactions between genotype and environment, with genetic differences reduced by rewilding. Variations in T cells are driven primarily by genotype and B cells by environment. We find that immune variation was associated with altered parasite burdens. The results indicate that while nonheritable influences interact with genetic factors to affect immune variation, the effect of genotype remains powerful, especially for cytokine activity. A most recent study describes how rewinding matures B cell populations in particular. 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.