# Defining resistance and tolerance mechanisms in hyper-susceptible mice during M. tuberculosis infection

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2021 · $230,979

## Abstract

Project Summary
 Infections with Mycobacterium tuberculosis (Mtb) result in over 1.5 million deaths annually. Unfortunately,
there are no effective vaccines against pulmonary disease and current treatment regimens extend to at least
six months. There is an urgent need to develop new approaches to treatment, such as host-directed therapies,
that shorten treatment time and improve disease prognosis. To effectively develop new host-directed
therapies, we must understand how protective pathways function mechanistically and determine how they
interact with other immune networks. Using targeted genetic interaction studies, we recently discovered a
strong synthetic lethal interaction between the NADPH phagocyte oxidase (Phox) and Caspase1/11
(Casp1/11) during Mtb infection. Loss of either locus individually results in minimal survival defects yet
combining deletions resulted in rapid disease progression within 4 weeks post-infection. These infections were
characterized by increased Mtb in the lungs and dysregulated inflammatory signals including IL1a and IL10.
 Here the failed host response in Phox/Casp1/11 animals will be dissected. The susceptibility of
Phox/Casp1/11 animals might be due to loss of resistance mechanisms that directly control pathogen replication
and/or tolerance mechanisms that control overall host health during infection. We hypothesize that loss of Phox
and Caspase1/11 together results in dysregulated immune defense cascades leading to both failed resistance
and tolerance during Mtb infection. We have developed models that allow the effects of tolerance and
resistance to be quantified. In Aim1 defects in the antimicrobial resistance of Phox/Casp1/11 animals will be
measured using ex vivo and in vivo models designed to report directly on bacterial growth and fitness
independently of inflammatory differences. In Aim 2 tolerance responses in Phox/Casp1/11 animals will be
examined using an in vivo model that normalizes Mtb levels between animals and directly quantifies how
dysregulated inflammation contributes to susceptibility. Determining the contribution of resistance and
tolerance to the susceptibility of Phox/Casp1/11 animals is a critical step to define the immune networks
modulated by Phox and Casp1/11 and examine their potential as host-directed therapy targets.

## Key facts

- **NIH application ID:** 10092102
- **Project number:** 5R21AI148961-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Andrew Olive
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $230,979
- **Award type:** 5
- **Project period:** 2020-01-29 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092102

## Citation

> US National Institutes of Health, RePORTER application 10092102, Defining resistance and tolerance mechanisms in hyper-susceptible mice during M. tuberculosis infection (5R21AI148961-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092102. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*