title: Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism.
abstract: 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.
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Elks
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Brizee
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Vaart
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Fredericus J
authors.initials: FJ
authors.lastname: van Eeden
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Meijer
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D015538:Nitrosation; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000099162:Endothelial PAS Domain-Containing Protein 1