Journal
FEBS JOURNAL
Volume 289, Issue 3, Pages 671-681Publisher
WILEY
DOI: 10.1111/febs.16209
Keywords
ferroptosis; granuloma; Hmox1; iron; mycobacteria
Categories
Funding
- Chinese Scholarships Council
- University of Sydney Fellowship [G197581]
- NSW Ministry of Health under the NSW Health Early-Mid Career Fellowships Scheme [H18/31086]
- NHMRC Centre of Research Excellence in Tuberculosis Control [APP1153493]
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Iron homeostasis is crucial for the host-pathogen interface, with Haem oxygenase 1 playing a critical role in regulating iron levels. In zebrafish-Mycobacterium marinum infection, Hmox1a is shown to protect the host by reducing iron accumulation and cell death induced by the infection.
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.
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