# Project 2: Innate immune responses triggered by M. tuberculosis

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $477,440

## Abstract

Project Summary/Abstract (Project 2, Cox)
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, remains a major cause of human
morbidity and mortality, particularly in the developing world. Chronic M. tuberculosis infection requires long-
term interactions between the bacterium and host immune system, and tissue macrophages play key roles in
the outcome of infection. The goal of this project is to identify the interactions between M. tuberculosis and
macrophages at the molecular level, and to understand how they influence bacterial killing. Our previous work
has identified a macrophage pathway activated by M. tuberculosis infection that induces both antibacterial
responses of macrophages and, paradoxically, anti-viral responses that inhibit immunity. In this proposal, we
seek to dissect these two antagonistic responses activated by this pathway, which requires the host factor
STING, with the long-term goal of developing host-directed therapeutics that push the balance in favor of TB
immunity. In Aim 1 we investigate the molecular mechanisms by which the STING pathway targets M.
tuberculosis to autophagy, a powerful anti-infection pathway of the host. In Aim 2, we explore the role of
Galectin-9 in host defense against M. tuberculosis infection, as this carbohydrate-binding protein is a prime
candidate for collaborating with STING to promote autophagy. In Aim 3, we seek to understand the mechanism
by which STING-activated interferon responses function to promote M. tuberculosis infection. Importantly, both
the autophagy targeting and anti-viral signaling pathways are controlled by important kinases, indicating that
post-translational modification of host proteins play important roles in mediating these effects. Thus, our
proposed use of cutting-edge proteomics in Aim 4 to identify the proteins modified by these enzymes during
infection represents a powerful way to uncover mechanisms by which macrophages control infection.
Importantly, our work is highly synergistic with the other projects and cores that make up this Program Project,
and the comparisons of host responses elicited by M. tuberculosis with those induced by L. monocytogenes
and L. pneumophila will allow us to identify pathogen-specific responses as well as common responses
induced by diverse intracellular bacterial pathogens. These studies will not only provide deeper mechanistic
understanding of how autophagy and anti-viral signaling control infection, but may also uncover novel host
pathways that function to eliminate intracellular bacterial pathogens.

## Key facts

- **NIH application ID:** 9977106
- **Project number:** 5P01AI063302-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JEFFERY S COX
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,440
- **Award type:** 5
- **Project period:** 2004-12-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977106

## Citation

> US National Institutes of Health, RePORTER application 9977106, Project 2: Innate immune responses triggered by M. tuberculosis (5P01AI063302-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977106. Licensed CC0.

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