Haem oxygenase limits Mycobacterium marinum infection‐induced detrimental ferrostatin‐sensitive cell death in zebrafish
Kaiming Luoa b c d, Roland Stockerb d e f, Warwick J. Brittona c g h, Kazu Kikuchib d i j, Stefan H. Oehlersa c k l✉
- aTuberculosis Research Program at the Centenary Institute The University of Sydney Camperdown NSW Australia
- bVictor Chang Cardiac Research Institute Darlinghurst NSW Australia
- cTuberculosis Research Program at the Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- dVictor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
- eThe Heart Research Institute Newtown NSW Australia
- fThe Heart Research Institute, Newtown, NSW, Australia
- gDepartment of Clinical Immunology Royal Prince Alfred Hospital Camperdown NSW Australia
- hDepartment of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
- iNational Cerebral and Cardiovascular Center Suita, Osaka Japan
- jNational Cerebral and Cardiovascular Center, Suita, Osaka, Japan
- kInfection, Immunity and Inflammation Theme and Sydney Institute for Infectious Diseases The University of Sydney Camperdown NSW Australia
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Abstract
Iron homeostasis is essential for both sides of the host-pathogen interface. Restricting access of iron slows bacterial growth while iron is also a necessary cofactor for host immunity. Haem oxygenase 1 (HMOX1) is a critical regulator of iron homeostasis that catalyses the liberation of iron during degradation of haem. It is also a stress-responsive protein that can be rapidly upregulated and confers protection to the host. Although a protective role of HMOX1 has been demonstrated in a variety of diseases, the role of HMOX1 in Mycobacterium tuberculosis infection is equivocal across experiments with different host-pathogen combinations. Here, we use the natural host-pathogen pairing of the zebrafish-Mycobacterium marinum infection platform to study the role of zebrafish haem oxygenase in mycobacterial infection. We identify zebrafish Hmox1a as the relevant functional paralog of mammalian HMOX1 and demonstrate a conserved role for Hmox1a in protecting the host from M. marinum infection. Using genetic and chemical tools, we show zebrafish Hmox1a protects the host against M. marinum infection by reducing infection-induced iron accumulation and ferrostatin-sensitive cell death.