# Necrosis in Pulmonary TB granulomas: dynamics, mechanisms, and therapies

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $665,784

## Abstract

PROJECT SUMMARY/ABSTRACT
 Most humans are resistant to Mycobacterium tuberculosis (Mtb) and form granulomas that limit inflammatory
tissue damage. Nevertheless, tuberculosis (TB) remains a leading infectious cause of death globally because a
fraction of infected individuals develops massive necrotic granulomas and transmit Mtb via aerosols. This
outcome of Mtb infection is relatively uncommon among immunocompetent humans, and its mechanisms are
poorly characterized. We will study both host vulnerability (predisposition to necrotization of TB granulomas) and
Mtb virulence determinants (the necrosis-inducing factor) to determine how their interactions lead to necrosis in
susceptible but otherwise immunocompetent hosts.
 We will address this major knowledge gap using a well-characterized mouse model developed in our laboratory
that recapitulates the formation of organized human-like necrotic pulmonary TB granulomas (mice with the
susceptibility allele of the sst1(super-susceptibility to tuberculosis, sst1) locus) Our recent studies reveal that
inadequate antioxidant defense (AOD) drives an aberrant response of the sst1 mutant macrophages to TNF and
induce hyperactivity of type I interferon pathway (IFN-I). This mouse model also provides a unique opportunity
to study the role of a recently discovered Tuberculosis Necrotizing Toxin (TNT).
 The major premise of this application is that impaired stress resilience of macrophages due to inadequate
antioxidant defense (AOD) is exploited by Mtb to subvert local immunity within pulmonary TB granulomas of
immunocompetent hosts and induce necrosis. We will investigate: (i) Crosstalk of Myc and IFN-I pathways in the
deregulation of antioxidant response in activated macrophages. (ii) Host regulators of the anti-oxidant response
and necrosis in vivo. This aim will address our hypothesis about the hierarchy of the antioxidant defense and
IFN-I pathways in vivo and test whether boosting the antioxidant defense prevents the granuloma necrotization
and reduce the IFN-I hyperactivity. (iii) Role of the Mtb Tuberculosis Necrotizing Toxin (TNT) in driving necrosis
in TB granulomas of the susceptible but immunocompetent hosts.
 The ultimate goal of our studies is to develop mechanistic interventions to target necrosis in TB granulomas in
order to overcome a major obstacle to the sterilization of TB lesions with antibiotics. This will improve the
outcomes of TB chemotherapy and prevent the evolution and spread of drug resistant TB.

## Key facts

- **NIH application ID:** 10791847
- **Project number:** 5R01HL126066-07
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Igor Kramnik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,784
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791847

## Citation

> US National Institutes of Health, RePORTER application 10791847, Necrosis in Pulmonary TB granulomas: dynamics, mechanisms, and therapies (5R01HL126066-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10791847. Licensed CC0.

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