Schild, Y., Mohamed, A., Wootton, E.J. et al. (2 more authors) (2020) Hif‐1alpha stabilisation is protective against infection in zebrafish comorbid models. The FEBS Journal, 287 (18). pp. 3925-3943. ISSN 1742-464X
Abstract
Multi‐drug‐resistant tuberculosis is a worldwide problem, and there is an urgent need for host‐derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia‐inducible factor‐1α (Hif‐1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif‐1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings, and it remains unclear whether Hif‐1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif‐1α on neutrophil behaviour in a comorbid setting by combining two well‐characterised in vivo zebrafish models – TB infection (Mycobacterium marinum infection) and sterile injury (tailfin transection). Using a local Mm infection near to the tailfin wound site caused neutrophil migration between the two sites that was reduced during Hif‐1α stabilisation. During systemic Mm infection, wounding leads to increased infection burden, but the protective effect of Hif‐1α stabilisation remains. Our data indicate that Hif‐1α stabilisation alters neutrophil migration dynamics between comorbid sites and that the protective effect of Hif‐1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host‐derived target against TB infection.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, (https://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | hypoxia; HIF; comorbid; Zebrafish; Mycobacteria |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 105570/Z/14/Z |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 22 Jun 2020 09:43 |
Last Modified: | 20 Oct 2020 09:22 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1111/febs.15433 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:162036 |