Effects of microbial exposure on TB pathogenesis

University Of Minnesota, Minneapolis MN

Investigators

Abstract

Tuberculosis (TB) is the leading cause of death by a bacterial disease worldwide. Differences in lung microenvironments, including the granuloma, influence the support and suppression of Mycobacterium tuberculosis (Mtb). While factors that impact microenvironment specific immune responses and Mtb sterility in the lung are incompletely understood, recent studies have shown that the microbiome takes an active role in shaping the immune response. Both lung and gut microbiomes have been shown to influence disease outcome in influenza, cystic fibrosis, asthma, cancer, and COPD. The dominant animal model used in TB is the mouse. While laboratory breeding of mice in specific pathogen free (SPF) and hygienic conditions has increased reproducibility, it has also removed much of the microbial exposure experienced by free-living organisms. Daily encounters with microbes help sculpt the immune system for a robust response against new pathogens. Unfortunately, the immune system of SPF mice lacks effector differentiated CD8+ memory T cells, which are critical cell types for an immediate response to infection. It is unknown how prior experience to microbes impacts TB progression. This proposal leverages a novel mouse model (‘dirty’ mouse model) that creates multiple exposures to diverse microbes to shape the immune response in SPF mice. Microbially experienced pet store mice will be housed with C3HeB/FeJ SPF mice; thereby, transferring both commensal and pathogenic microbes between animals. C3HeB/FeJ mouse strain is selected as it forms multiple types of TB granulomas similar to human TB. The overall goal of this project is to determine how prior diverse microbial experiences influence the course of TB infection (‘dirty’ vs. SPF mice). The central hypothesis is that the lung and gut microbiomes of dirty C3HeB/FeJ mice will maintain equilibrium in the face of infection and shape the immune system to resist and control Mtb as compared to SPF mice. This proposal will define changes to 1) lung and gut microbiota diversity, 2) locations and interactions of microbiota inside granulomas and lungs, 3) innate and adaptive immune cell populations, and 4) IL-23 pathway, a critical host response in the control of TB, in dirty and SPF mice. The dirty mouse model will serve as a complement to existing small animal models of TB to reveal new biomarkers and host-directed treatments to TB that are influenced upon prior microbial experience. The outlined studies push the boundaries of our current understanding of TB pathogenesis and may ultimately show TB as a disease that is defined by intimate interactions between the pathogen, host, and microbiota.