# PROJECT 1: Identification of host and bacterial pathways that control tuberculosis pathogenesis in humans

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $735,403

## Abstract

PROJECT 1: IDENTIFICATION OF HOST AND BACTERIAL PATHWAYS THAT CONTROL TB
PATHOGENESIS IN HUMANS
SUMMARY
Phagocytes of the mammalian innate immune system, in particular macrophages, form the first line of
defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and
eradicate invaders. In addition to having direct antimicrobial activity, macrophages also initiate and shape
powerful inflammatory responses that dramatically influence disease. Bacterial pathogens, however, have
evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues.
Indeed, the inflammatory pathways robustly elicited by Mycobacterium tuberculosis (Mtb) – the etiological
agent of the devastating human disease tuberculosis (TB) and the focus of Project 1 – work to promote
bacterial growth and TB disease. However, the host genes and cellular pathways that dictate the outcome
of infection are not entirely clear. There is growing evidence that the earliest interactions of Mtb with two
very different subsets of lung macrophages, alveolar and “recruited” macrophages, are critical for TB
control, but our understanding of the response of alveolar macrophages to Mtb has been limited due to the
difficulty in studying these tissue resident lung macrophages. In Project 1, we will use new cellular models of
alveolar macrophages coupled with unbiased, systematic approaches to identify the specific molecular
networks that underly infection of these different macrophage types. In collaboration with the Technology
Core, we will use this information to make predictions about bacterial infectivity that will be tested in human
samples and mouse models of infection in an iterative fashion to model host response during infection.
These results, and those from Project 2, will be integrated by the Data Management and Bioinformatics and
Modeling Cores with existing -omics and human GWAS datasets to identify host and bacterial signatures that
correlate significantly with clinical pathogenesis. Importantly, we will focus our functional testing on pathways
that are shared between bacterial and viral responses (with Project 2) to understand the mechanisms that lead
to synergies during bacterial-viral co-infection.

## Key facts

- **NIH application ID:** 10550001
- **Project number:** 2U19AI135990-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JEFFERY S COX
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $735,403
- **Award type:** 2
- **Project period:** 2018-08-17 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10550001

## Citation

> US National Institutes of Health, RePORTER application 10550001, PROJECT 1: Identification of host and bacterial pathways that control tuberculosis pathogenesis in humans (2U19AI135990-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10550001. Licensed CC0.

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