Abstract
Regulation of host microRNA (miRNA) expression is a contested node that controls the host immune response to mycobacterial infection. The host must overcome concerted subversive efforts of pathogenic mycobacteria to launch and maintain a protective immune response. Here we examine the role of miR-126 in the zebrafish model of Mycobacterium marinum infection and identify a protective role for this infection-induced miRNA through multiple effector pathways. Specifically, we analyse the impact of the miR-126 knockdown-induced tsc1a and cxcl12a/ccl2/ccr2 signalling axes during early host-M. marinum interactions. We find a strong detrimental effect of tsc1a upregulation that renders zebrafish embryos susceptible to higher bacterial burden and increased cell death despite dramatically higher recruitment of macrophages to the site of infection. We demonstrate that infection-induced miR-126 suppresses tsc1 and cxcl12a expression thus improving macrophage function early in infection, partially through activation of mTOR signalling and strongly through preventing the recruitment of Ccr2+ permissive macrophages, resulting in the recruitment of protective tnfa-expressing macrophages. Together our results demonstrate an important role for infection-induced miR-126 in shaping an effective immune response to M. marinum infection in zebrafish embryos.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding The work was supported by a Meat and Livestock Australia Grant (P.PSH.0813) to KdS, KMP, and ACP; Higher Degree Research scholarship (P.PSH.0813) to KW, University of Sydney Fellowship (G197581) and NSW Ministry of Health under the NSW Health Early-Mid Career Fellowships Scheme (H18/31086) to SHO; the National Health and Medical Research Council Centre of Research Excellence in Tuberculosis Control (APP1153493) and The University of Sydney DVCR award to WJB.
