The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction

Appelmelk, B J and den Dunnen, J and Driessen, N N and Ummels, R and Pak, M and Nigou, J and Larrouy-Maumus, G and Gurcha, S S and Movahedzadeh, F and Geurtsen, J and Brown, E J and Smeets, M M E and Besra, G S and Willemsen, P T J and Lowary, T L and van Kooyk, Y and Maaskant, J J and Stoker, N G and van der Ley, P and Puzo, G and Vandenbroucke-Grauls, C and Wieland, C W and van der Poll, T and Geijtenbeek, T B H and van der Sar, A M and Bitter, W (2008) The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction. CELLULAR MICROBIOLOGY, 10 (4). pp. 930-944.

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Pathogenic mycobacteria have the ability to persist in phagocytic cells and to suppress the immune system. The glycolipid lipoarabinomannan (LAM), in particular its mannose cap, has been shown to inhibit phagolysosome fusion and to induce immunosuppressive IL-10 production via interaction with the mannose receptor or DC-SIGN. Hence, the current paradigm is that the mannose cap of LAM is a crucial factor in mycobacterial virulence. However, the above studies were performed with purified LAM, never with live bacteria. Here we evaluate the biological properties of capless mutants of Mycobacterium marinum and M. bovis BCG, made by inactivating homologues of Rv1635c. We show that its gene product is an undecaprenyl phosphomannose-dependent mannosyltransferase. Compared with parent strain, capless M. marinum induced slightly less uptake by and slightly more phagolysosome fusion in infected macrophages but this did not lead to decreased survival of the bacteria in vitro, nor in vivo in zebra fish. Loss of caps in M. bovis BCG resulted in a sometimes decreased binding to human dendritic cells or DC-SIGN-transfected Raji cells, but no differences in IL-10 induction were observed. In mice, capless M. bovis BCG did not survive less well in lung, spleen or liver and induced a similar cytokine profile. Our data contradict the current paradigm and demonstrate that mannose-capped LAM does not dominate the Mycobacterium-host interaction.

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