Research Article: Hypoxia Inducible Factor Signaling Modulates Susceptibility to Mycobacterial Infection via a Nitric Oxide Dependent Mechanism

Date Published: December 19, 2013

Publisher: Public Library of Science

Author(s): Philip M. Elks, Sabrina Brizee, Michiel van der Vaart, Sarah R. Walmsley, Fredericus J. van Eeden, Stephen A. Renshaw, Annemarie H. Meijer, David S. Schneider.


Tuberculosis is a current major world-health problem, exacerbated by the causative pathogen, Mycobacterium tuberculosis (Mtb), becoming increasingly resistant to conventional antibiotic treatment. Mtb is able to counteract the bactericidal mechanisms of leukocytes to survive intracellularly and develop a niche permissive for proliferation and dissemination. Understanding of the pathogenesis of mycobacterial infections such as tuberculosis (TB) remains limited, especially for early infection and for reactivation of latent infection. Signaling via hypoxia inducible factor α (HIF-α) transcription factors has previously been implicated in leukocyte activation and host defence. We have previously shown that hypoxic signaling via stabilization of Hif-1α prolongs the functionality of leukocytes in the innate immune response to injury. We sought to manipulate Hif-α signaling in a well-established Mycobacterium marinum (Mm) zebrafish model of TB to investigate effects on the host’s ability to combat mycobacterial infection. Stabilization of host Hif-1α, both pharmacologically and genetically, at early stages of Mm infection was able to reduce the bacterial burden of infected larvae. Increasing Hif-1α signaling enhanced levels of reactive nitrogen species (RNS) in neutrophils prior to infection and was able to reduce larval mycobacterial burden. Conversely, decreasing Hif-2α signaling enhanced RNS levels and reduced bacterial burden, demonstrating that Hif-1α and Hif-2α have opposing effects on host susceptibility to mycobacterial infection. The antimicrobial effect of Hif-1α stabilization, and Hif-2α reduction, were demonstrated to be dependent on inducible nitric oxide synthase (iNOS) signaling at early stages of infection. Our findings indicate that induction of leukocyte iNOS by stabilizing Hif-1α, or reducing Hif-2α, aids the host during early stages of Mm infection. Stabilization of Hif-1α therefore represents a potential target for therapeutic intervention against tuberculosis.

Partial Text

Pulmonary tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem and is a key priority for infectious disease research. The burden of TB has been exacerbated by the increasing occurrence of Mtb strains with resistance to multiple drug treatments, prioritising the need for understanding of the mechanistic basis of host-pathogen interactions during pathogenesis of disease in order to identify novel therapeutic strategies [1]. Upon infection Mtb are rapidly phagocytosed by host leukocytes, but are able to evade bacterial killing mechanisms and utilize the leukocytes as a niche in which to proliferate and disseminate [2]. Leukocyte infection initiates the recruitment of uninfected macrophages, neutrophils and T-cells, to form highly organised structures known as granulomas [3], [4]. Mtb within granulomas can persist for many years and may eventually escape and disseminate during clinical reactivation, causing active disease [5]. The pathogenesis of both initial infection and reactivation of latent infection are not well understood, and further research into host signaling pathways at these stages may uncover novel, host-derived targets for therapeutic intervention against Mtb.

The rise in prevalence of multi-drug resistant TB creates an urgent need for novel, host-targeting therapies to complement existing antibiotics and to combat currently untreatable strains of Mtb [41], [42]. Using a well-established zebrafish/Mm infection model of TB, we have identified a new anti-mycobacterial leukocyte phenotype being driven by Hif-1α stabilization and consequent iNOS activity. Our data identify that in vivo manipulation of Hif-α, a ubiquitous host-signaling pathway, can affect specific cellular mechanisms of pathogen handling, tipping the host-pathogen balance in favour of the host to decrease mycobacterial infection.




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