Interception of host angiogenic signalling limits mycobacterial growth

Using a model of tuberculosis in zebrafish, granuloma formation is shown to coincide with hypoxia and angiogenesis; furthermore, the pharmacological inhibition of the pro-angiogenic VEGF pathway reduces infection burden, suggesting a possible treatment strategy in patients with the disease. Angiogenesis in tuberculous granulomas Tuberculosis infections are often associated with the generation of masses of inflamed tissue known as tuberculous granulomas. Using intravital imaging in the zebrafish– Mycobacterium marinum infection model, this study shows that granuloma formation coincides with hypoxia and the induction of the pro-angiogenic molecule VEGF. Pharmacological inhibition of the VEGF pathway prevents vascularization of the granuloma tissue and reduces infection burden. Anti-angiogenic therapies also synergize with anti-tubercular treatments, suggesting possible alternatives to conventional therapy in the event of antibiotic resistance. Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis 1 , 2 . Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish– Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis 2 . Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations 3 . Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.