Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility

Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish- Mycobacterium marinum infection model is used extensively to model many aspects of human- M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings. Funding This work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Consellería de Economía, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).