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.

Public Health Relevance

M. tuberculosis (Mtb) persists in the host causing latent infection (LTBI) that is asymptomatic difficult to treat and can reactivate causing tuberculosis disease. Iron (Fe) deprivation drives Mtb into a non-replicating state, similar to that of Mtb in LTBI. To aid development of effective therapies against LTBI this proposal studies the mechanisms by which Fe-starved Mtb remains viable and persists in the host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI144503-02
Application #
10126800
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mendez, Susana
Project Start
2020-03-12
Project End
2022-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Rutgers University
Department
Surgery
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103