Nitric oxide in defence against mycobacterial infection
Can we enhance the capacity of host immune cells to kill mycobacteria via production of reactive nitrogen species?
- 2011 - 2013
- Annemarie Meijer
- European Respiratory Society
With a personal fellowship from the European Respiratory Society Dr. Phil Elks joined the group of Annemarie Meijer at the IBL to study the role of hypoxia inducible factor and nitric oxide signaling using the zebrafish tuberculosis model. This project helped him to acquire a group leader position at the University of Sheffield, from where he continues to collaborate with the Meijer lab.
Tuberculosis (TB) is a mycobacterial disease that forms a global health threat. Due to emerging strains with multi-drug resistance there is an urgency of developing novel therapeutic interventions. Mycobacteria have the ability to subvert microbicidal mechanisms of the host immune cells that they parasitize. We are exploring possibilities of pharmaceutical reprogramming of the immune system such that their capacity to kill these intracellular pathogens is restored. To this end we use a zebrafish model of TB that mimics hallmarks of the human disease. In this project we investigated if host resistance to mycobacterial infection can be enhanced by manipulating hypoxia inducible factor (HIF) signaling. We found that increasing HIF signaling during early stages of infection primes neutrophils with higher levels of reactive nitrogen species (RNS). This nitrosative defence response, which is mediated by inducible nitric oxide synthase (iNOS), decreases mycobacterial infection in the zebrafish host. However, mycobacteria are able to counteract this response during the normal cause of infection. This works shows that targeting either the host signaling pathways or the bacterial virulence mechanisms involved in this host-pathogen interaction could be explored as strategies for developing future therapeutics against TB.
- Elks PM, Renshaw SA, Meijer AH, Walmsley SR, van Eeden FJ (2015) Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. Dis Model Mech. 8:1349-60
- Elks PM, van der Vaart M, van Hensbergen V, Schutz E, Redd MJ, Murayama E, Spaink HP, Meijer AH (2014) Mycobacteria Counteract a TLR-Mediated Nitrosative Defense Mechanism in a Zebrafish Infection Model. PLoS ONE 9:e100928
- Elks PM, Brizee S, van der Vaart M, Walmsley SR, Van Eeden F, Renshaw SA, Meijer AH (2013) Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism. PLoS Pathog 9:e1003789