Regulation of mucosal immune responses by helminth infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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, we have calculated the relative effect sizes of diet, clinical lab parameters, blood transcriptional profiles and parasitic infection status on the gut microbiota communities. 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. Individuals from villages with higher prevalences of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition were most strongly associated with different villages and the effects of helminth infection status on the microbiome varies by village. Longitudinal changes in the microbiome in response to albendazole anthelmintic treatment was observed in both helminth infected and uninfected individuals. Inference of bacterial population replication rates from origin of replication analysis identified specific replicating taxa associated with helminth infection. These results indicated that helminth effects on the microbiota was highly dependent on context and effects of albendazole on the microbiota can be confounding for the interpretation of deworming studies. Furthermore, a substantial quantity of the microbiome remains unannotated and this large dataset from an indigenous population associated with helminth infections is a valuable resource for future studies. We have also 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. 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. 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.