Hypoxic Signalling and Tuberculosis

01 January 2014

IBL-researcher Phil Elks in the group of Annemarie Meijer won the Cell Observatory Publication of the Year 2013. He received the award for his paper in PLoS Pathogens, showing that activation of hypoxia signaling protects against mycobacterial infection.

Tuberculosis is a mycobacterial disease that was a major cause of death until the discovery of antibiotics in the mid-twentieth century. However, TB is once again on the rise, with the emergence of strains that are multi-drug resistant. Mycobacteria are specialists in evading immune cell killing and use host immune cells as a niche in which they can proliferate and survive latently, until subsequent reactivation and spreading causing life-threatening disease. Pharmaceutical reprogramming of the immune system to kill intracellular mycobacteria would represent a therapeutic strategy, effective against currently untreatable strains and less susceptible to drug resistance.

Phil Elks and colleagues used an in vivo zebrafish model of TB to show that manipulation of the host genetic pathway responsible for detecting low oxygen levels (hypoxia) causes a decrease in mycobacterial infection. This antimicrobial effect was due to a priming of immune cells with increased levels of nitric oxide, a molecule that is used by immune cells to kill bacteria. These results show that in vivo manipulation of a host-signaling pathway aids the host in combatting mycobacterial infection, identifying hypoxic signaling as a potential target for future therapeutics against TB.

**Figure 1:** Schematic of the effect of modulating hypoxia signaling during early mycobacterial infection in zebrafish ( *Danio rerio*). Hypoxia signalling was modulated using dominant active and dominant negative constructs of the transcription factors Hypoxia Inducible Factor (HIF) alpha 1 and 2. Increasing HIF-1α signalling or decreasing HIF-2α signalling increased nitric oxide (NO) levels in neutrophils prior to infection of zebrafish embryos with *Mycobacterium marinum*, used as a model for tuberculosis. Several days later these embryos had a reduced bacterial burden compared with the control group.

This project was a collaborative effort of researchers at the Universities of Leiden and Sheffield. Phil Elks was a post-doc in the lab of Dr Stephen Renshaw at The University of Sheffield, where he investigated hypoxia-induced genetic signalling (HIF signalling) and its role in wound-induced inflammation. In 2011, he acquired an European Respiratory Society (ERS) Long Term Fellowship to move to Leiden for studying the role of HIF signalling in infection in the group of Dr. Annemarie Meijer.

In 2013, Phil was awarded a Vice-Chancellor’s Fellowship to return to Sheffield to set up his own research group. The collaboration with Leiden will be continued. Leiden and Sheffield Universities also work together in the European Training Network FishForPharma and Sheffield researcher Tomacz Prajsnar recently acquired a Marie Curie fellowship to move to Leiden for a collaborative project on Staphylococcus aureus infection.

Phil Elks will present the results of the PLoS Pathogens publication in This Week’s Discoveries on the 25^th of February.

Link to the Cell Observatory, shared research facility for the Life Sciences: http://cellobservatory.leidenuniv.nl/