# Dissecting the genetic basis of protective immunity to tuberculosis in diverse hosts

> **NIH NIH DP2** · DUKE UNIVERSITY · 2024 · $966,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10879738
- **Project number:** 4DP2AI183152-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Clare Margaret Smith
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $966,000
- **Award type:** 4N
- **Project period:** 2021-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879738

## Citation

> US National Institutes of Health, RePORTER application 10879738, Dissecting the genetic basis of protective immunity to tuberculosis in diverse hosts (4DP2AI183152-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10879738. Licensed CC0.

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