Universiteit Leiden

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Proefschrift

Exploitation of host chemokine signalling by pathogenic mycobacteria

Promotores: A.H. Meijer, H.P. Spaink

Auteur
V. Torraca
Datum
17 november 2016
Links
Thesis in Leiden Repository

Mycobacterium tuberculosis, the agent of TB, is one of the deadliest human pathogens, infecting one third of the global population. Establishment of infection by mycobacteria relies on complex interactions with host innate immune cells, especially macrophages. Once engulfed by macrophages, mycobacteria “usurp” the host cell machineries to facilitate dissemination and to establish an intracellular niche for survival and replication. To investigate how mycobacteria force the immune cells to support infection, we explored the chemokine pathway, best known for its capability to induce cell migration. To dissect the interplay between immune cells and the pathogen, we modelled human TB using the zebrafish-Mycobacterium marinum natural host-pathogen pair, which is attractive for the excellent optical accessibility of the zebrafish larvae and the possibility to apply genetic tools to impair the chemokine signaling. We show that depletion of either CXCR3 or CXCR4 axes are beneficial to the host. Exploitation of CXCR3 signaling leads to macrophage recruitment and to transcriptional changes in macrophages that make them more permissive for mycobacterial intracellular persistence. Activating CXCR4 signaling triggers instead vascularization of the nascent tuberculous granulomas, which in turn supports expansion of the infection. Therefore, inhibitions of these pathways represent promising host-directed therapeutic avenues to counteract mycobacterial diseases.