Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis. Here we examine the development and consequences of vascular dysfunction of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model.
Using larval and adult zebrafish infected with M. marinum, we have illustrated a bidirectional interaction between granuloma formation and vascular dysfunction. We have shown that limiting infection-induced 1) angiogenesis with VEGFR-targeting drugs, 2) vascular permeability via disruption of the ANG-2/TIE-2 signalling pathway, or 3) thrombocyte activation with anti-platelet drugs are potential host directed therapies that reduce infection burden and protect the host from mycobacterial infection. I will discuss the mechanisms of action for each of these interactions and the implications of these findings in the context of novel host directed therapies for mycobacterial infection.