# The essential role of manganese in persistence of M. tuberculosis under iron starvation.

> **NIH NIH R21** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $250,821

## Abstract

Mycobacterium tuberculosis (Mtb) is responsible for over 1 million deaths each year. A key factor in Mtb
success is its ability to resist immune defense mechanisms and establish latent TB infection (LTBI) in
immunocompetent hosts. In LTBI, the bacilli can persist for decades in a slow-to-non-replicating state that is
refractory to treatment, as antibiotics generally target cell functions associated with active growth and
proliferation. Persons with LTBI can develop active TB disease at any time after the initial infection, thereby
constituting an enormous reservoir of new TB cases. How the host-bacterial interplay leads to establishment of
LTBI and enables prolonged survival of Mtb in the host is not clear.
 During infection, Mtb must adapt to essential micronutrient limitation imposed by the host as part of an
antimicrobial strategy known as “nutritional immunity”. Our recent work showed that a key component of
nutritional immunity against Mtb is a plethora of host iron(Fe)-sequestration and Fe-restriction factors
concentrated in the center of tuberculous granulomas, likely resulting in strong Fe deprivation for the infecting
Mtb. We also found that Fe deprivation in vitro induces Mtb to adopt a quiescent state reminiscent of bacilli in
LTBI, tolerant to antibiotics and capable of surviving for a long time in the absence of environmental Fe.
Furthermore, we have shown that Fe-starved persistent Mtb efficiently recovers and replicates when Fe
availability increases, which is reminiscent of reports of reactivation of LTBI in Mtb-infected humans receiving Fe-
supplementation. Based on these observations we postulate that Fe restriction by nutritional immunity may trigger
the development of a quiescent state in infecting Mtb and promote the establishment of LTBI. Thus, we
hypothesize that impeding Mtb ability to persist under Fe-deprivation will decrease its capacity to retain long-term
viability in the host and may constitute a novel approach to combat Mtb persistence during LTBI.
 Our most recent studies identified availability of manganese (Mn) as a determinant factor in survival of Fe-
deprived Mtb. To identify strategies to reduce Mtb persistence under Fe-starvation, this proposal seeks to
elucidate the mechanisms by which Mn sustains viability of Fe-deprived Mtb. Accomplishing the aims will open
new paths for therapeutic research on pathogen and/or host directed therapeutics strategies to target the metal
requirements of Mtb for persistence.

## Key facts

- **NIH application ID:** 9894232
- **Project number:** 1R21AI144503-01A1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Gloria Marcela Rodriguez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $250,821
- **Award type:** 1
- **Project period:** 2020-03-12 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894232

## Citation

> US National Institutes of Health, RePORTER application 9894232, The essential role of manganese in persistence of M. tuberculosis under iron starvation. (1R21AI144503-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894232. Licensed CC0.

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