# M. tuberculosis strain-dependent interactions with host cells

> **NIH NIH U19** · UNIVERSITY OF WASHINGTON · 2021 · $450,831

## Abstract

Tuberculosis (TB) is a multifaceted disease that has extensive variation in clinical manifestations despite being
the product of infection with a single pathogen, Mycobacterium tuberculosis. The extensive genetic diversity in
human and Mycobacterium tuberculosis genomes responsible for differences in clinical outcomes represent
modifications of host-pathogen interactions that are key to pathogenesis. Understanding the basis for these
heterogenous responses will uncover new mechanisms of virulence and resistance and will impact treatment
and diagnostics. Unfortunately, the challenges of studying the mechanisms of differential outcomes of infection
in humans not only includes identification of correlations between host/pathogen genotypes with phenotypes in
human populations, but also the subsequent identification of the mechanisms that are causal for disease which
require studying them in the laboratory without the pathogen’s natural host organism. This Program takes
advantage of unique, ongoing genome-wide association studies (GWAS) that have identified both human and
pathogen variants that are associated with heterogenous clinical responses in two different human populations.
To determine the mechanisms underlying these variations, we will employ a powerful set of experimental
assays, including new proteomics-based scanning platform to probe host responses during experimental
macrophage infection that is orthogonal to traditional mRNA profiling, in order to broadly search for changes in
host innate immune pathways that correlate with disease outcomes associated with these clinical strains.
Based on our preliminary data, we hypothesize that many of these interactions occur early during infection and
are mediated by proteins secreted by M. tuberculosis. In this proposal, we focus primarily on correlations
between two unique sets of clinical bacterial variants, strains that are associated greater transmission of
pulmonary TB disease and strains that are more prone to dissemination to distal sites in the body. An
unexpected theme from both of these sets of strains is the prevalence of TB proteins secreted by the ESX
systems expressed in M. tuberculosis. Both the ESX-1 and ESX-5 secretion systems of M. tuberculosis are
key virulence determinants required for intracellular growth and for eliciting distinct innate immune responses
during macrophage infection. A central hypothesis is that the set of bacterial proteins that influence disease
outcomes are enriched for secreted proteins that mediate interactions between pathogen and host
macrophages. To test this hypothesis, we will collaborate with Cores A and B to use an integrative approach
to combine genetic data from the M. tuberculosis GWAS datasets with genetic and proteomic screen to identify
causal genes that mediate interactions with macrophages. We will use these same technologies to collaborate
with Projects 2 and 3 to identify proteins/pathways responsible for host resistance and bacterial
diss...

## Key facts

- **NIH application ID:** 10271172
- **Project number:** 1U19AI162583-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JEFFERY S COX
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,831
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271172

## Citation

> US National Institutes of Health, RePORTER application 10271172, M. tuberculosis strain-dependent interactions with host cells (1U19AI162583-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271172. Licensed CC0.

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