TY - JOUR T1 - Hypoxia signaling modulates neutrophil nitric oxide in a zebrafish tuberculosis model JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P3051 AU - Philip Elks AU - Michiel van der Vaart AU - Fredericus van Eeden AU - Herman Spaink AU - Sarah Walmsley AU - Annemarie Meijer AU - Stephen Renshaw Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P3051.abstract N2 - Tuberculosis is on the rise due to the increasing prevalence of multi-drug resistant strains. Further understanding of the host response to Mycobacterium tuberculosis (Mtb) may lead to the identification of host-derived factors as potential therapeutic targets, circumventing bacterial resistance. We have identified hypoxic signalling, via hypoxia inducible factor 1 alpha Hif-1α, as a host-derived signalling pathway that modulates the host response to infection.There is a lack of whole organism, in vivo, models in which to study TB. Zebrafish embryos are transparent and fluorescent transgenic lines allow detailed imaging of leukocytes. Mycobacterium marinum (Mm), a close relative of Mtb, is becoming a well-accepted model for the study of TB. Hif-modulated embryos were infection with Mm and the host response was investigated.Hif signalling was observed in infected macrophages early in pathogenesis but not at later stages. Stabilisation of Hif-1α led to decreased bacterial burden, an effect that was demonstrated to be dependent on inducible nitric oxide synthase (iNOS), a bacterial killing mechanism of leukocytes. Hif-1α stabilisation primed neutrophils with increased iNOS, allowing them to better deal with Mm infection. Furthermore, live Mm were able to decrease neutrophil iNOS levels over the timecourse of pathogenesis, indicative of a reprogramming of leukocytes by Mm to allow bacterial survival.Our data show that Hif and iNOS are important host derived immune modulators that are initially activated after Mm infection only to be downregulated later in pathogenesis. Maintaining Hif/iNOS levels may be a novel therapeutic strategy that circumvents the problem of multi-drug resistance. ER -