Manipulation of host hypoxia signalling as a therapeutic strategy for mycobacterial infection (360G-Wellcome-105570_Z_14_Z)

Therapeutic strategies that target pathogens are failing and TB has re-emerged as a leading cause of global mortality with 1.3 million deaths yearly (WHO, 2012). There is an unmet need for novel, host-targeted therapeutics that upregulate the immune response to infection to complement current antimicrobials. Tissue hypoxia is a potent activator of leukocyte responses via activation of host hypoxia inducible factor (HIF) signalling. I hypothesise HIF signalling is a host-response that if therapeu tically activated, will improve the host response to infection. My overarching aim is to test this hypothesis in vivo. In a zebrafish mycobacterial infection model, I have shown that genetic upregulation of HIF prior to infection leads to higher levels of bactericidal nitric oxide in neutrophils and to reduced burden of infection. These data support an emerging paradigm where neutrophil killing of mycobacteria is essential for disease control and identify HIF and NO as effective targets for int ervention against mycobacterial infection. Combining genetic approaches with dynamic live-imaging, I will address the following hypotheses: 1) HIF activation is a host antibacterial response that is actively downregulated by Mm at a critical tipping-point of infection; and 2) Pharmacological upregulation of leukocyte Hif is a viable therapeutic strategy for mycobacterial infection.