Abstract
The human response to Mycobacterium tuberculosis (Mtb) infection is affected by the availability of iron (Fe), which is necessary for proper immune cell function and is essential for the growth and virulence of bacteria. Increase in host Fe levels promotes Mtb growth and tuberculosis (TB) pathogenesis, while Fe-supplementation to latently infected, asymptomatic individuals is a significant risk factor for disease reactivation. However, the effect of Fe-supplementation on the host immunity during latent Mtb infection remains unclear, due partly to the paucity in availability of animal models that recapitulate key pathophysiological features seen in humans. We have demonstrated that rabbits can develop non-progressive latency similar to infected humans. In this study, using this model we have evaluated the effect of Fe-supplementation on the bacterial growth, disease pathology, and immune response. Systemic and lung Fe parameters, gene expression profile, lung bacterial burden, and disease pathology were determined in the Mtb-infected/Fe- or placebo-supplemented rabbits. Results show that Fe-supplementation to Mtb-infected rabbits did not significantly change the hematocrit and Hb levels, although it elevated total Fe in the lungs. Expression of selected host iron- and immune-response genes in the blood and lungs was perturbed in Mtb-infected/Fe-supplemented rabbits. Iron-supplementation during acute or chronic stages of Mtb infection did not significantly affect the bacterial burden or disease pathology in the lungs. Data presented in this study is of significant relevance for current public health policies on Fe-supplementation therapy given to anemic patients with latent Mtb infection.
Highlights
About a third of the world’s population is estimated to be infected with Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB) [1,2]
The human response to Mtb infection is affected by the availability of iron (Fe), which is necessary for the proper function of the immune system [5]
An average hematocrit level of 42% and Hb content of ~14 g/L was observed at all time-points (Supplementary Figure S2), and no significant difference in either the hematocrit or Hb levels was observed in Mtb-infected rabbits with Fe- or placebo supplementation
Summary
About a third of the world’s population is estimated to be infected with Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB) [1,2]. The World Health Organization (WHO) has identified Fe deficiency as the most common nutritional disorder worldwide and has developed a strategy to eradicate anemia in TB-endemic countries that includes increasing Fe intake through food fortification programs (https://www.who.int/nutrition/ publications/en/ida_assessment_prevention_control.pdf) This program does not screen individuals for prior exposure to Mtb before starting therapy. Mtb mutant for mbtK, a mycobactin synthase gene involved in siderophore production, is defective for Fe-acquisition and showed attenuated growth in vitro and in infected mouse lungs [15] These findings clearly show that Mtb utilizes several mechanisms to acquire Fe from the host and highlight the importance of Fe acquisition for the growth and virulence of Mtb. treatment of Mtb-infected mice with Fe promoted bacterial growth in tissues and Fe-supplementation to anemic individuals has been associated with reactivation of LTBI [16,17,18]. We have used this LTBI rabbit model to investigate the effect of moderate Fe-supplementation on the immune response and outcome of pulmonary Mtb infection
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