Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity

E.J.M. Stoop, A. K. Mishra, N.N. Driessen, G. van Stempvoort, P. Bouchier, T. Verboom, L.M. van Leeuwen, M. Sparrius, S.A. Raadsen, M. van Zon, N.N. van der Wel, G.S. Besra, J.J.G. Geurtsen, W. Bitter, B.J. Appelmelk, A.M. van der Sar

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M.tuberculosis orthologue, disruption of M.marinummptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M.marinummptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatismptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity. © 2013 John Wiley & Sons Ltd.
Original languageEnglish
Pages (from-to)2093-2108
JournalCellular Microbiology
Volume15
Issue number12
DOIs
Publication statusPublished - 2013

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Mannans
Innate Immunity
Virulence
Zebrafish
Tuberculosis
Mannose
Mannosyltransferases
Mycobacterium
Nuclear Family
Mycobacterium tuberculosis
Immunoblotting
Communicable Diseases
Embryonic Structures
lipoarabinomannan
lipomannan

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Stoop, E. J. M., Mishra, A. K., Driessen, N. N., van Stempvoort, G., Bouchier, P., Verboom, T., ... van der Sar, A. M. (2013). Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity. Cellular Microbiology, 15(12), 2093-2108. https://doi.org/10.1111/cmi.12175
Stoop, E.J.M. ; Mishra, A. K. ; Driessen, N.N. ; van Stempvoort, G. ; Bouchier, P. ; Verboom, T. ; van Leeuwen, L.M. ; Sparrius, M. ; Raadsen, S.A. ; van Zon, M. ; van der Wel, N.N. ; Besra, G.S. ; Geurtsen, J.J.G. ; Bitter, W. ; Appelmelk, B.J. ; van der Sar, A.M. / Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity. In: Cellular Microbiology. 2013 ; Vol. 15, No. 12. pp. 2093-2108.
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title = "Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity",
abstract = "The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M.tuberculosis orthologue, disruption of M.marinummptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M.marinummptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatismptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity. {\circledC} 2013 John Wiley & Sons Ltd.",
author = "E.J.M. Stoop and Mishra, {A. K.} and N.N. Driessen and {van Stempvoort}, G. and P. Bouchier and T. Verboom and {van Leeuwen}, L.M. and M. Sparrius and S.A. Raadsen and {van Zon}, M. and {van der Wel}, N.N. and G.S. Besra and J.J.G. Geurtsen and W. Bitter and B.J. Appelmelk and {van der Sar}, A.M.",
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Stoop, EJM, Mishra, AK, Driessen, NN, van Stempvoort, G, Bouchier, P, Verboom, T, van Leeuwen, LM, Sparrius, M, Raadsen, SA, van Zon, M, van der Wel, NN, Besra, GS, Geurtsen, JJG, Bitter, W, Appelmelk, BJ & van der Sar, AM 2013, 'Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity' Cellular Microbiology, vol. 15, no. 12, pp. 2093-2108. https://doi.org/10.1111/cmi.12175

Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity. / Stoop, E.J.M.; Mishra, A. K.; Driessen, N.N.; van Stempvoort, G.; Bouchier, P.; Verboom, T.; van Leeuwen, L.M.; Sparrius, M.; Raadsen, S.A.; van Zon, M.; van der Wel, N.N.; Besra, G.S.; Geurtsen, J.J.G.; Bitter, W.; Appelmelk, B.J.; van der Sar, A.M.

In: Cellular Microbiology, Vol. 15, No. 12, 2013, p. 2093-2108.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity

AU - Stoop, E.J.M.

AU - Mishra, A. K.

AU - Driessen, N.N.

AU - van Stempvoort, G.

AU - Bouchier, P.

AU - Verboom, T.

AU - van Leeuwen, L.M.

AU - Sparrius, M.

AU - Raadsen, S.A.

AU - van Zon, M.

AU - van der Wel, N.N.

AU - Besra, G.S.

AU - Geurtsen, J.J.G.

AU - Bitter, W.

AU - Appelmelk, B.J.

AU - van der Sar, A.M.

PY - 2013

Y1 - 2013

N2 - The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M.tuberculosis orthologue, disruption of M.marinummptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M.marinummptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatismptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity. © 2013 John Wiley & Sons Ltd.

AB - The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M.tuberculosis orthologue, disruption of M.marinummptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M.marinummptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatismptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity. © 2013 John Wiley & Sons Ltd.

U2 - 10.1111/cmi.12175

DO - 10.1111/cmi.12175

M3 - Article

VL - 15

SP - 2093

EP - 2108

JO - Cellular Microbiology

JF - Cellular Microbiology

SN - 1462-5814

IS - 12

ER -