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Effect of Deletion or Overexpression of the 19-Kilodalton Lipoprotein Rv3763 on the Innate Response to Mycobacterium tuberculosis

Graham R. Stewart,^, Katalin A. Wilkinson,^, Sandra M. Newton, Susan M. Sullivan,^¶ Olivier Neyrolles,^|| John R. Wain, Janisha Patel,^# Kara-Lee Pool, Douglas B. Young, and Robert J. Wilkinson^*

Center for Molecular Microbiology and Infection and Wellcome Trust Center for Research in Clinical Tropical Medicine, Imperial College London, London, United Kingdom

Received 11 December 2004/ Returned for modification 10 February 2005/ Accepted 31 May 2005

The 19-kDa lipoprotein of Mycobacterium tuberculosis is an important target of the innate immune response. To investigate the immune biology of this antigen in the context of the whole bacillus, we derived a recombinant M. tuberculosis H37Rv that lacked the 19-kDa-lipoprotein gene (19) and complemented this strain by reintroduction of the 19-kDa-lipoprotein gene on a multicopy vector to produce 19::pSMT181. The 19 strain multiplied less well than 19::pSMT181 in human monocyte-derived macrophages (MDM) (P = 0.039). Surface expression of major histocompatibility complex class II molecules was reduced in phagocytes infected with M. tuberculosis; this effect was not seen in cells infected with 19. 19 induced lower interleukin 1ß (IL-1ß) secretion from monocytes and MDM. Overexpression of the 19-kDa protein increased IL-1ß, IL-12p40, and tumor necrosis factor alpha secretion irrespective of phagocyte maturity. These data support reports that the 19-kDa lipoprotein has pleiotropic effects on the interaction of M. tuberculosis with phagocytes. However, this analysis indicates that in the context of the whole bacillus, the 19-kDa lipoprotein is only one of a number of molecules that mediate the innate response to M. tuberculosis.

Editor: J. L. Flynn

G.R.S. and K.A.W. contributed equally to this work.

Present address: School of Biological and Medical Sciences, University of Surrey, Guildford, United Kingdom.

Present address: Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.

^¶ Present address: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.

^|| Present address: Unite de Genetique Mycobacterienne, Institut Pasteur, Paris, France.

^# Present address: University of Warwick Medical School, Coventry, United Kingdom.

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