# Foam cells as drug targets in tuberculosis

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $787,897

## Abstract

Lipid-laden macrophages (foam cells) are central to maintaining chronic tuberculosis (TB) infection. Foam cells
provide a favorable niche for survival of Mycobacterium tuberculosis, because antimicrobial functions are
generally down-regulated in these cells. Moreover, foam cells induce tissue damage and caseation, and facilitate
TB transmission. Indeed, the extent of TB-induced tissue damage is closely correlated with foam cell abundance
in lesions. The overarching hypothesis of this proposal is that blocking foam cell formation will facilitate
macrophage-mediated clearance of M. tuberculosis infection. We recently discovered that, unlike the cholesteryl-
ester-rich foam cells found in atherosclerotic lesions, foam-cell-rich and necrotic areas of tuberculous
granulomas are particularly enriched in triglycerides. Given the different nature of the storage lipid, the underlying
lipid accumulation mechanisms in tuberculous foam cells must differ substantially from those known to occur
during atherogenesis. Thus, TB-specific interventions are needed to impede foam cell formation in TB. Infection
with M. tuberculosis is associated with dysregulation of two cellular pathways involved in triglyceride
homeostasis: the first, which is pro-lipogenic, includes two kinases, protein kinase B and mTOR complex 1
(Akt/mTORC1); the second, which is anti-lipogenic, includes AMP-activated protein kinase and the NAD+-
dependent deacetylases called sirtuins (AMPK/SIRT). We propose a two-aim plan utilizing clinical samples from
human donors and experimental infections of macrophages ex vivo and of a mouse strain producing necrotic
tuberculous lung lesions (C3HeB/FeJ). These experiments will characterize: (i) the effect of anti-lipogenic
treatments on antimycobacterial functions of human macrophages infected ex vivo; (ii) the relationship between
activation of these pathways and control of clinical M. tuberculosis infection; and (iii) the role of anti-lipogenic
treatments as adjunctive therapy for TB in C3HeB/FeJ mice. The overall objective of this proposal is to discover
druggable targets in the pro-lipogenic and anti-lipogenic pathways, with the long-term goal of shortening the
duration of TB treatment and improving TB-related immunopathology. This proposal is expected to lead to clinical
trials of novel host-directed therapeutics against TB. More generally, these studies are expected to reveal the
potential for pharmacological interventions targeting maladaptive macrophage responses in non-atherogenic
diseases and to stimulate their pursuit.

## Key facts

- **NIH application ID:** 10205167
- **Project number:** 5R01HL149450-03
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Maria Laura Gennaro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $787,897
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205167

## Citation

> US National Institutes of Health, RePORTER application 10205167, Foam cells as drug targets in tuberculosis (5R01HL149450-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10205167. Licensed CC0.

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