# Relationship between the iron response and the pathogenic potential of M. tuberculosis

> **NIH NIH R03** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $79,500

## Abstract

Clinical isolates of Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis
(TB), show diversity in transmission, pathogenicity and elicited immune responses. However, the microbial
factors associated with high prevalence of particular Mtb lineages and their enhanced pathogenic potential
are not well understood. Over the last two decades Mtb strains belonging to the W/Beijing lineage have
become increasingly prevalent, representing 50% of isolates in East Asia and about 13% of all Mtb isolates
worldwide. W/Beijing strains are also overrepresented among multidrug resistant isolates and are
significantly associated with human immunodeficiency virus (HIV) infection. Thus, understanding the factors
contributing to the success of this lineage is important for designing better diagnostics and intervention
strategies against TB. One determinant of Mtb ability to thrive in vivo and cause disease is its response to
the stringent iron (Fe) limitation imposed by the host. Fe is an essential micronutrient for Mtb proliferation
that is sequestered by the host as part of nutritional immunity. Bacterial adaptation to Fe limitation is
connected to virulence in two ways. First, obtaining sufficient Fe from the host is needed for bacterial
proliferation. Second, Fe limitation is a signal for microbial pathogens, including Mtb, to induce production of
pathogenicity factors. Our preliminary studies showed that Mtb clinical isolates are highly heterogeneous in
their ability to adapt to Fe limitation in vitro. In particular, we found that a W/Beijing strain HN878, which is
hypervirulent in animal models of infection, is deficient in growth in low Fe in vitro due to a natural genomic
insertion of the IS6110 mobile element into a Fe storage gene bfrA. We also found that HN878 has a
heightened transcriptional response to Fe limitation in vitro. In this project we propose to investigate the link
between hypersensitivity to Fe deficiency and expression of virulence-related genes and pathogenicity
functions in HN878. These parameters will be compared between the original HN878 strain and a HN878
strain where bfrA expression and ability to grow in low Fe have been restored. We will also examine the
significance of IS6110 insertion in other members of the W/Beijing family. The results will aid in
understanding the basis for Mtb heterogeneous interactions with the host and also the biological
implications of IS6110 transposition – two important aspects of Mtb biology that are largely underexplored.

## Key facts

- **NIH application ID:** 9876908
- **Project number:** 5R03AI144257-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Gloria Marcela Rodriguez
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,500
- **Award type:** 5
- **Project period:** 2019-02-19 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876908

## Citation

> US National Institutes of Health, RePORTER application 9876908, Relationship between the iron response and the pathogenic potential of M. tuberculosis (5R03AI144257-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9876908. Licensed CC0.

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