# Host Pathogen Variation & TB Pathogenesis

> **NIH NIH U19** · UNIVERSITY OF WASHINGTON · 2021 · $2,638,886

## Abstract

Hurdles for controlling tuberculosis (TB) include developing a highly efficacious vaccine, preventing
transmission and infection in endemic areas, and discovering drug treatment regimens that work rapidly and
kill dormant bacilli within macrophages. After exposure to Mycobacterium tuberculosis (Mtb), outcomes vary
widely including resistance, asymptomatic latent infection, active pulmonary disease, and disseminated
infections including TB meningitis (TBM). This heterogeneity complicates clinical treatment decisions with
regards to choosing the number of drugs and duration of treatment. This broad clinical spectrum also presents
a unique opportunity for understanding the biological mechanisms that control TB pathogenesis. A major
source of heterogeneity is a combination of genetic variation in both humans and Mtb that are evolving under
constant selective pressure. Our overall program objective is to use genetic, genomic, proteomic, and
bioinformatic strategies to discover host and pathogen variants of genes and gene products that are
associated with TB clinical outcomes and to determine how these variants interact to regulate molecular,
cellular, and in vivo functions. Our strategy is anchored upon two powerful cohorts in Vietnam and Uganda
(Core A) that capture the full spectrum of resistance to traditional LTBI (latent TB infection), LTBI, pulmonary
TB disease, and disseminated disease in the form of TBM. Core A examines paired host and Mtb genetic
data and the association with these diverse clinical outcomes. In Project 1, we use genetic and new
proteomic strategies to examine how the Mtb genes and variants identified by Core A function and how the
encoded proteins interact with and regulate macrophage responses. In Project 2, we use human genetic
methods along with proteomic strategies in macrophages to uncover regulatory host genes and variants that
are associated with resistance to Mtb infection and/or disseminated TB. In Project 3, we examine in vivo
mechanisms of transmission and dissemination that are attributed to specific host genes and pathways and
Mtb variants, employing a new and powerful mouse model of infection that recapitulates many of the
manifestations that occur in human TB. Core B uses pathway-driven and novel bioinformatics approaches to
integrate the genetic results from Core A with the multiple large-scale and diverse datasets to dynamically
identify and prioritize pathways and protein networks for functional testing. Together, this multidisciplinary
program and strategy will enable us to test our overall hypothesis that variants of Mtb and host genes dictate
heterogeneous clinical outcomes and encode factors that interact with and alter innate immune cells. We will
use genetic, genomic, proteomic, and bioinformatic strategies to examine variation in Mtb and its paired
human host to examine mechanisms of resistance and susceptibility to infection and disease with discovery of
biomarkers for clinical management and novel i...

## Key facts

- **NIH application ID:** 10271168
- **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:** $2,638,886
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271168

## Citation

> US National Institutes of Health, RePORTER application 10271168, Host Pathogen Variation & TB Pathogenesis (1U19AI162583-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271168. Licensed CC0.

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