# Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis

> **NIH NIH F32** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2022 · $79,153

## Abstract

PROJECT SUMMARY/ABSTRACT
Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB) and the leading cause of death
from a single infectious agent. An estimated 10 million people developed TB disease in 2017, demonstrating an
urgent need to new therapeutic approaches, including host-directed therapy (HDT) to halt infection and
progression of active TB. Macrophages often serve as the first line of defense against invading pathogens.
However, M.tb modulates macrophage cell signaling pathways to induce an environment beneficial to its
intracellular survival. The strategies employed by M.tb are an active area of investigation. The overall goal of
the laboratory is to identify intracellular master regulators of inflammation and metabolic intermediates that
dictate human macrophage responses to M.tb. Previous work in our lab revealed that M.tb interaction with the
macrophage mannose receptor (MR) activates peroxisome proliferator-activated receptor gamma (PPARγ), a
transcription factor that dampens the inflammatory response and is associated with increased M.tb growth. The
proposed research plan will investigate the hypothesis that MR ligation by M.tb initiates the cAMP signaling
pathway leading to PPARγ activation, resulting in enhanced survival of M.tb in macrophages. The Specific Aims
are to: 1) Determine the role of phosphodiesterases (PDEs) in regulating PPARγ activity through the cAMP
signaling pathway during M.tb infection of hMDMs, 2) Determine the role of Protein Kinase A (PKA) and
Exchange Protein Directly Activated by cAMP 1 (Epac1) in regulating PPARγ activity following M.tb-elicited
cAMP production in hMDMs, and 3) Determine the effects of MR/cAMP/PKA/Epac1/PPARγ signaling on M.tb
pathogenesis. The proposed project will further elucidate the signaling pathway(s) downstream of MR ligation
by M.tb, an area only minimally investigated. In addition, this project uses an innovative, newly developed
humanized mouse model to study human MR in vivo devoid of the murine MR which is a confounding factor to
data analysis. Investigation of the cAMP pathway is expected to identify new, druggable host cell targets for HDT
against TB. This research plan affords me the ability to learn new scientific techniques, new models to study
infectious diseases, detailed data analysis and the training to shape the direction of this project and my career.
The training plan outlines career development activities including opportunities to improve my scientific
presentation and communication skills, grantsmanship, mentoring and teaching skills. The research and training
will take place at the Texas Biomedical Research Institute with a deep commitment to scientific training,
evidenced by numerous journal clubs, seminars and full support of the Texas Biomed Association for Trainees.
Texas Biomed has various core facilities, high containment research labs for M.tb work both in vitro and in mice
and NHPs, and all resources needed for excellent scientific...

## Key facts

- **NIH application ID:** 10369686
- **Project number:** 5F32AI152348-03
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Chrissy Leopold Wager
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $79,153
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369686

## Citation

> US National Institutes of Health, RePORTER application 10369686, Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis (5F32AI152348-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10369686. Licensed CC0.

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