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Infection and Immunity, July 2008, p. 3027-3036, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01663-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Phenolic Glycolipid of Mycobacterium tuberculosis Differentially Modulates the Early Host Cytokine Response but Does Not in Itself Confer Hypervirulence{triangledown}

Daniel Sinsimer,1,2 Gaelle Huet,3 Claudia Manca,1 Liana Tsenova,1 Mi-Sun Koo,1 Natalia Kurepina,4 Bavesh Kana,5 Barun Mathema,4 Salvatore A. E. Marras,6 Barry N. Kreiswirth,4 Christophe Guilhot,3 and Gilla Kaplan1*

Laboratory of Mycobacterial Immunity and Pathogenesis,1 TB Center,4 Department of Molecular Genetics, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, 225 Warren St., Newark, New Jersey 07103,6 Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, 225 Warren St., Newark, New Jersey 07103,2 Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, Université Paul Sabatier de Toulouse, Centre National de la Recherche Scientifique, Toulouse, France,3 MRC/NHLS/WITS Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, School of Pathology of the University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa5

Received 13 December 2007/ Returned for modification 23 February 2008/ Accepted 17 April 2008

Mycobacterium tuberculosis possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinical M. tuberculosis isolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group of M. tuberculosis strains with an intact pks1-15 gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinical M. tuberculosis isolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence of M. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.

* Corresponding author. Mailing address: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, 225 Warren St., Newark, NJ 07103. Phone: (973) 854-3220. Fax: (973) 854-3221. E-mail:kaplangi{at}umdnj.edu

{triangledown} Published ahead of print on 28 April 2008.

Editor: J. L. Flynn

Infection and Immunity, July 2008, p. 3027-3036, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01663-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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