Comparative and Functional Genomic Analyses of Iron Transport and Regulation in Leptospira spp.

Laboratoire des Spirochètes, Institut Pasteur, 28 rue du docteur Roux, 75724 Paris Cedex 15, France.
Journal of Bacteriology (Impact Factor: 2.81). 12/2006; 188(22):7893-904. DOI: 10.1128/JB.00711-06
Source: PubMed


The spirochetes of the Leptospira genus contain saprophytic and pathogenic members, the latter being responsible for leptospirosis. Despite the recent sequencing of the genome of the pathogen L. interrogans, the slow growth of these bacteria, their virulence in humans, and a lack of genetic tools make it difficult to work with these pathogens. In contrast, the development of numerous genetic tools for the saprophyte L. biflexa enables its use as a model bacterium. Leptospira spp. require iron for growth. In this work, we show that Leptospira spp. can acquire iron from different sources, including siderophores. A comparative genome analysis of iron uptake systems and their regulation in the saprophyte L. biflexa and the pathogen L. interrogans is presented in this study. Our data indicated that, for instance, L. biflexa and L. interrogans contain 8 and 12 genes, respectively, whose products share homology with proteins that have been shown to be TonB-dependent receptors. We show that some genes involved in iron uptake were differentially expressed in response to iron. In addition, we were able to disrupt several putative genes involved in iron acquisition systems or iron regulation in L. biflexa. Comparative genomics, in combination with gene inactivation, gives us significant functional information on iron homeostasis in Leptospira spp.

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Available from: Claudine Medigue, Feb 26, 2015
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    • "HlyC (TlyC) has been reported to have hemolysin activity (Zhang et al., 2005), but later studies reported it not to have hemolytic activity (Carvalho et al., 2009) and hence the exact functional role of this protein is yet to be elucidated. Iron is an essential nutrient for pathogenic leptospires and the transport of heme or other iron-containing molecules by Gram-negative bacteria often relies on the active transport through TonB dependent OM receptors (Asuthkar et al., 2007; Louvel et al., 2006). After binding, transport of the nutrient across the OM in to the periplasm is an energy-dependent step "
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    ABSTRACT: Abstract Pathogenic Leptospira species are important human and animal pathogen that causes leptospirosis, with more than half a million cases reported annually but little is known regarding the true incidence of leptospirosis due to the limitations in diagnosis. Proteins embedded in the outer membrane are found to be prime drug targets due to its key role as receptors for cellular communication and gatekeepers for iron and substrate transport across cell membranes. The major key issues to be addressed to overcome the disease burden of leptospirosis are: need to identify the genes that turn on in vivo; development of rapid diagnostic methods to facilitate the early diagnosis and to develop a universal vaccine. Recent whole genome sequencing of Leptospira species and development of in silico analysis tools have led to the identification of a large number of leptospiral virulence genes, metabolic pathways and surface protein secretion systems that represent potential new targets for the development of anti-leptospiral drug, vaccine and diagnostic strategies. This review surveys the different types of outer membrane proteins (OMPs) of Leptospira and combines all the novel features of OMPs reported till date and put forth some views for future research.
    Critical Reviews in Microbiology 05/2013; 41(1). DOI:10.3109/1040841X.2013.787387 · 6.02 Impact Factor
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    • "Although further experimentation is necessary to confirm the association of the proteins, this observation suggests that at least one of the sphingomyelinase-like proteins is secreted via the TolC-based type I secretory pathway (Jenewein et al., 2009). Another TolC homologue (LA3927/LIC13135) was also noted as potentially functioning in sphingomyelinase secretion (Louvel et al., 2006). "
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    ABSTRACT: Culture supernatants of leptospiral pathogens have long been known to haemolyse erythrocytes. This property is due, at least in part, to sphingomyelinase activity. Indeed, genome sequencing reveals that pathogenic Leptospira species are richly endowed with sphingomyelinase homologues: five genes have been annotated to encode sphingomyelinases in Leptospira interrogans. Such redundancy suggests that this class of genes is likely to benefit leptospiral pathogens in their interactions with the mammalian host. Surprisingly, sequence comparison with bacterial sphingomyelinases for which the crystal structures are known reveals that only one of the leptospiral homologues has the active site amino acid residues required for enzymic activity. Based on studies of other bacterial toxins, we propose that leptospiral sphingomyelinase homologues, irrespective of their catalytic activity, may possess additional molecular functions that benefit the spirochaete. Potential secretion pathways and roles in pathogenesis are discussed, including nutrient acquisition, dissemination, haemorrhage and immune evasion. Although leptospiral sphingomyelinase-like proteins are best known for their cytolytic properties, we believe that a better understanding of their biological role requires the examination of their sublytic properties as well.
    Microbiology 03/2012; 158(Pt 5):1137-46. DOI:10.1099/mic.0.057737-0 · 2.56 Impact Factor
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    • "The functions of TonB dependent OMP family proteins are difficult to infer bioinformatically but have been examined by systematically knocking out the genes in L. biflexa, which is much easier to manipulate genetically than is L. interrogans. Examination of the growth dependence on iron sources of L. biflexa knockouts revealed a ferioxamine receptor and a FecA-like receptor for iron salts, which has a close homologue in L. interrogans (Louvel et al., 2006). An additional TonB dependent OMP has been designated HbpA (LIC20151), based on its ability to bind hemin (Asuthkar et al., 2007). "
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    ABSTRACT: Summary Leptospira is a genus of spirochaetes that includes organisms with a variety of lifestyles ranging from aquatic saprophytes to invasive pathogens. Adaptation to a wide variety of environmental conditions has required leptospires to acquire a large genome and a complex outer membrane with features that are unique among bacteria. The most abundant surface-exposed outer membrane proteins are lipoproteins that are integrated into the lipid bilayer by amino-terminal fatty acids. In contrast to many spirochaetes, the leptospiral outer membrane also includes lipopolysaccharide and many homologues of well-known beta-barrel transmembrane outer membrane proteins. Research on leptospiral transmembrane outer membrane proteins has lagged behind studies of lipoproteins because of their aberrant behaviour by Triton X-114 detergent fractionation. For this reason, transmembrane outer membrane proteins are best characterized by assessing membrane integration and surface exposure. Not surprisingly, some outer membrane proteins that mediate host-pathogen interactions are strongly regulated by conditions found in mammalian host tissues. For example, the leptospiral immunoglobulin-like (Lig) repeat proteins are dramatically induced by osmolarity and mediate interactions with host extracellular matrix proteins. Development of molecular genetic tools are making it possible to finally understand the roles of these and other outer membrane proteins in mechanisms of leptospiral pathogenesis.
    Molecular Microbiology 06/2010; 77(4). DOI:10.1111/j.1365-2958.2010.07262.x · 4.42 Impact Factor
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