Mycobacterium leprae Phenolglycolipid-1 Expressed by Engineered M. bovis BCG Modulates Early Interaction with Human Phagocytes

CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France.
PLoS Pathogens (Impact Factor: 7.56). 10/2010; 6(10):e1001159. DOI: 10.1371/journal.ppat.1001159
Source: PubMed


The species-specific phenolic glycolipid 1 (PGL-1) is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells.

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Available from: Caroline Demangel
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    • "Activation of different stress pathways might result not only in a change in phenotype but also in genetic adaptations (Beaumont et al., 2009; Ensminger et al., 2012). pks1 is part of the DIM+PGL locus, responsible for the synthesis of phenolic glycolipids (PGLs) and linked to the virulence of certain strains of M. tuberculosis (Reed et al., 2004; 2007; Sinsimer et al., 2008) and M. leprae (Tabouret et al., 2010). Based on our data, we concluded that the macrophage lifestyle has selected mycobacteria that have a non-functional pks1. "
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    • "If this mechanism is operating in mycobacterial cell invasion, low MASP-2 levels would be insufficient to avoid subsequent infection. Surely this hypothesis needs to be tested in a functional setting, maybe using the recently achieved bioengineered BCG bacillus [36]. Otherwise in malaria, the ingestion of hemozoin could be beneficial to control for dyserithropoiesis [44]. "
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    • "kansasii, M. gastri, M. ulcerans, M. marinum, M. microti and M. haemophilum) [1], [2]. These substances, located in the outermost layer of the mycobacterial cell envelope, have been shown to play important functions in the pathogenicity of these bacteria [3], [4], [5], [6]. PGL are composed of a mixture of long chain β-diols, esterified by multimethyl-branched fatty acids, named mycocerosic acids or phthioceranic acids depending on the configuration of the asymmetric centres bearing the methyl branches [1]. "
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