Zebrafishtsc1andcxcl12aincrease susceptibility to mycobacterial infection

Abstract

Regulation of host miRNA expression is a contested node that controls the host immune response to mycobacterial infection. The host must counter subversive efforts of pathogenic mycobacteria to launch a protective immune response. Here, we examine the role of miR-126 in the zebrafish–Mycobacterium marinuminfection model and identify a protective role for infection-induced miR-126 through multiple effector pathways. We identified a putative link between miR-126 and thetsc1aandcxcl12a/ccl2/ccr2signalling axes resulting in the suppression of non-tnfaexpressing macrophage accumulation at earlyM. marinumgranulomas. Mechanistically, we found a detrimental effect oftsc1aexpression that renders zebrafish embryos susceptible to higher bacterial burden and increased cell death via mTOR inhibition. We found that macrophage recruitment driven by thecxcl12a/ccl2/ccr2signalling axis was at the expense of the recruitment of classically activatedtnfa-expressing macrophages and increased cell death around granulomas. Together, our results delineate putative pathways by which infection-induced miR-126 may shape an effective immune response toM. marinuminfection in zebrafish embryos.