Abstract |
Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA ( miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas.
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Authors | Kathryn Wright, Kumudika de Silva, Karren M Plain, Auriol C Purdie, Tamika A Blair, Iain G Duggin, Warwick J Britton, Stefan H Oehlers |
Journal | PLoS pathogens
(PLoS Pathog)
Vol. 17
Issue 4
Pg. e1009186
(04 2021)
ISSN: 1553-7374 [Electronic] United States |
PMID | 33826679
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CXCL12 protein, human
- CXCR4 protein, human
- Chemokine CXCL12
- MicroRNAs
- Receptors, CXCR4
- mirn206 microRNA, zebrafish
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Topics |
- Animals
- Chemokine CXCL12
(immunology, metabolism)
- Gene Knockdown Techniques
(methods)
- MicroRNAs
(genetics)
- Mycobacterium Infections, Nontuberculous
(genetics, immunology)
- Mycobacterium marinum
(metabolism)
- Neutrophil Infiltration
(immunology)
- Receptors, CXCR4
(immunology, metabolism)
- Signal Transduction
(genetics, immunology)
- Zebrafish
(immunology)
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