PROJECT SUMMARY For hosts chronically infected with a pathogen, survival is ultimately determined by a carefully balanced host response that must include both resistance and disease tolerance mechanisms. “Resistance” involves antimicrobial pathways that directly control bacterial burden, while disease “tolerance” is comprised of mechanisms to withstand the cumulative damage of tissue damage that chronic infection entails. In the context of tuberculosis (TB), resistance pathways eventually break down, and Mycobacterium tuberculosis (Mtb) is able to persist in tissues long-term. At that point, disease tolerance is vital for regulating the immune response to prevent overt damage and ensure ultimate survival of the host. With the failure of current therapies that focus on directly targeting microbial pathways, this proposal instead focuses on identifying the mediators of host tolerance that may be leveraged to design new host-directed strategies. From preliminary studies through the Collaborative Cross (CC) panel, unlike standard inbred mouse strains, I found that the CC panel models the broad phenotypic spectrum of TB disease states observed in human cohorts. I identified CC genotypes that control a spectrum of phenotypes ranging from CC mice that are resistant and able to control bacterial burden, to CC mice that are highly susceptible and succumb to disease within a month of infection. While I found many disease traits were generally correlated, I also found CC strains harboring qualitatively distinct disease states, including several “outlier” genotypes where typical disease metrics were broken. For example, bacterial burden and weight loss are correlated in the standard C57BL/6J model of infection, yet among CC strains harboring 107 CFU in their lungs, I identified genotypes with a wide variation in weight loss and survival. Several genotypes showed limited pathology and could tolerate disease at high burden, while other CC genotypes exhibited weight loss and succumbed to disease at the same CFU. These data suggest that distinct genetic mechanisms underlie disease tolerance. In the New Innovator Award, this project will leverage these CC “outlier” strains as new models of disease tolerance to define the immunological, bacterial and host genetic mechanisms underpinning this essential and understudied component of protective immunity to pathogens. Overall, this work will provide new insights into disease tolerance that are relevant to genetically diverse hosts. Understanding the immunological and genetic mediators of disease tolerance will allow the rational design of novel host-directed strategies that may be applied to tuberculosis and other chronic infections.

PROJECT NARRATIVE Genetic diversity is a key factor underlying heterogenous disease states of tuberculosis. However, current mouse models fail to incorporate both genetic and phenotypic diversity. This proposal leverages diverse but reproducible Collaborative Cross mouse strains, bacterial reporters of infection and novel host-pathogen genetic mapping strategies to mechanistically define loci underlying disease tolerance. Overall, these novel and synergistic strategies will define new models of disease tolerance and set the roadmap for systematically interrogating host-pathogen genetic interactions underlying tuberculosis.