# Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB)

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $813,868

## Abstract

PROJECT SUMMARY
Tuberculosis (TB) is the 2nd leading cause of infectious disease mortality worldwide with ~1.5 million deaths in
2020. A hallmark of pulmonary TB is the propensity to form cavitary lesions in ~30-85% of patients. Cavities
provide an ideal environment for Mycobacterium tuberculosis (Mtb) replication, are associated with decreased
penetration of antibiotics, and can lead to irreversible lung damage. Importantly, they are associated with poor
clinical outcomes including acquired drug resistance and treatment failure. Cavities develop from progression
of necrotic lung granulomas; however, mechanisms underlying their formation are not clear. Improved
understanding of the inflammatory responses that drive tissue necrosis and the ability of antibiotics to achieve
therapeutic concentrations within necrotic granulomas are needed to 1) identify targets for host directed
therapies (HDT) that can limit tissue damage and 2) to optimize antibiotic regimens. Utilizing innovative
methods in imaging and spatial multiomics, we will map the distribution of transcriptional pathways and
biomediators associated with human necrotic granulomas and cavities and of newly implemented anti-TB
drugs in such lesions with an overall goal of providing critical new data to improve TB treatment
The long term objective of this research is to provide data to guide development of a tandem therapeutic
approach of optimizing anti-TB drug regimens based on their ability to reach bactericidal concentrations in all
lesion areas combined with host-targeted therapies to limit pathologic inflammation. The specific aims of this
proposal are to (1) identify the host metabolic and lipid phenotypes associated with each tissue region of
human necrotic lung granulomas; (2) utilize spatial transcriptomics and targeted imaging to identify
pathological programs associated with tissue necrosis in necrotic granulomas; and (3) utilize target site
pharmacokinetics (PK) and PK modeling to enhance understanding of newly implemented anti-TB drugs. The
aims of this project will be achieved by enrolling a unique cohort of patients with pulmonary TB undergoing
adjunctive surgery and subsequent study of their resected lung lesions. Scientific methods employed to carry
out our aims include the use of enhanced MALDI-2 mass spectrometry imaging (MSI), laser capture
microdissection (LCM) to isolate targeted granulomas regions for high-resolution metabolomics, lipidomics and
drug concentration assays, and novel spatial transcriptomics and advanced data analytic methods to integrate
spatially resolved multi-omics data sets and model target site PK data.
This proposal will directly address key priories in the TB research agenda including attaining a better
understanding of the determinants of M. tuberculosis control in granulomas and how anti-TB drugs localize and
penetrate into granulomas and cavities. Specific goals of the proposed work are to identify host inflammatory
pathways that can be exploite...

## Key facts

- **NIH application ID:** 10568147
- **Project number:** 1R01AI173946-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Russell Ryan Kempker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $813,868
- **Award type:** 1
- **Project period:** 2023-02-09 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10568147

## Citation

> US National Institutes of Health, RePORTER application 10568147, Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB) (1R01AI173946-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10568147. Licensed CC0.

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