Leptospiral LruA Is Required for Virulence and Modulates an Interaction with Mammalian Apolipoprotein AI

Zhang, Kunkun; Murray, Gerald L; Seemann, Torsten; Srikram, Amporn; Bartpho, Thanatchaporn; Sermswan, Rasana W.; Adler, Ben; Hoke, David E.

doi:10.1128/iai.01195-12

Cited by 26 publications

(15 citation statements)

References 46 publications

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“…The lack of involvement in disease pathogenesis by the majority of exoproteins is in agreement with the findings of previous studies on L. interrogans virulence genes which have demonstrated that the majority of genes are dispensable for virulence (27,68). Moreover, with the exception of a catalase gene (katE) (34) and a collagenase gene (24), the genes that have been demonstrated to be essential for virulence, such as HtpG (63), Loa22 (69), and those involved in motility (11,12), LPS biosynthesis (13), heme metabolism (70), and adhesion (71,72), have orthologues in the nonpathogenic species L. biflexa. In combination with the finding that the majority of L. interrogans exoproteins have orthologues in L. biflexa, this evidence further supports the theory that L. interrogans evolved from L. biflexa.…”

Section: Discussionmentioning

confidence: 67%

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

et al. 2015

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bLeptospirosis is a life-threatening and emerging zoonotic disease with a worldwide annual occurrence of more than 1 million cases. Leptospirosis is caused by spirochetes belonging to the genus Leptospira. The mechanisms of disease manifestation in the host remain elusive, and the roles of leptospiral exoproteins in these processes have yet to be determined. Our aim in this study was to assess the composition and quantity of exoproteins of pathogenic Leptospira interrogans and to construe how these proteins contribute to disease pathogenesis. Label-free quantitative mass spectrometry of proteins obtained from Leptospira spirochetes cultured in vitro under conditions mimicking infection identified 325 exoproteins. The majority of these proteins are conserved in the nonpathogenic species Leptospira biflexa, and proteins involved in metabolism and energy-generating functions were overrepresented and displayed the highest relative abundance in culture supernatants. Conversely, proteins of unknown function, which represent the majority of pathogen-specific proteins (presumably involved in virulence mechanisms), were underrepresented. Characterization of various L. interrogans exoprotein mutants in the animal infection model revealed host mortality rates similar to those of hosts infected with wild-type L. interrogans. Collectively, these results indicate that pathogenic Leptospira exoproteins primarily function in heterotrophic processes (the processes by which organisms utilize organic substances as nutrient sources) to maintain the saprophytic lifestyle rather than the virulence of the bacteria. The underrepresentation of proteins homologous to known virulence factors, such as toxins and effectors in the exoproteome, also suggests that disease manifesting from Leptospira infection is likely caused by a combination of the primary and potentially moonlight functioning of exoproteins.

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Section: Discussionmentioning

confidence: 67%

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

et al. 2015

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“…LruC was experimentally demonstrated to be an OM lipoprotein but was not exposed on the bacterial surface, it was located in the inner leaflet of the OM ( 84 ). In contrast, LruA was exposed on the leptospiral surface, with a possible role in the modulation of interactions with human apolipoprotein A-I (ApoA-I), contributing to leptospiral virulence ( 86 ). Furthermore, LruA was shown to be essential for L. interrogans virulence in the hamster model ( 86 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology

et al. 2017

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Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing leptospirosis, a public health problem with global implications. Thousands of people die every year due to leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) vaccine; however, success has been limited. A prospective vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to vaccine development.

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“…Previous studies have identified a number of biological processes that appear to be required for leptospiral virulence. These include genes involved in motility (30,36), heme utilization (18), lipopolysaccharide biosynthesis (40), stress resistance (25,41,42), and the host-pathogen interaction (43) and genes that are involved in a manner that has not yet been determined (44,45). However, previous research has also negated the requirement of putative virulence factors LipL32 (46), LipL41 (47), and LigB (48) in the animal infection model.…”

Section: Fig 4 the Lb139mentioning

confidence: 94%

A Putative Regulatory Genetic Locus Modulates Virulence in the Pathogen Leptospira interrogans

et al. 2014

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Limited research has been conducted on the role of transcriptional regulators in relation to virulence in Leptospira interrogans, the etiological agent of leptospirosis. Here, we identify an L. interrogans locus that encodes a sensor protein, an anti-sigma factor antagonist, and two genes encoding proteins of unknown function. Transposon insertion into the gene encoding the sensor protein led to dampened transcription of the other 3 genes in this locus. This lb139 insertion mutant (the lb139 ؊ mutant) displayed attenuated virulence in the hamster model of infection and reduced motility in vitro. Whole-transcriptome analyses using RNA sequencing revealed the downregulation of 115 genes and the upregulation of 28 genes, with an overrepresentation of gene products functioning in motility and signal transduction and numerous gene products with unknown functions, predicted to be localized to the extracellular space. Another significant finding encompassed suppressed expression of the majority of the genes previously demonstrated to be upregulated at physiological osmolarity, including the sphingomyelinase C precursor Sph2 and LigB. We provide insight into a possible requirement for transcriptional regulation as it relates to leptospiral virulence and suggest various biological processes that are affected due to the loss of native expression of this genetic locus.

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Leptospiral LruA Is Required for Virulence and Modulates an Interaction with Mammalian Apolipoprotein AI

Cited by 26 publications

References 46 publications

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology

A Putative Regulatory Genetic Locus Modulates Virulence in the Pathogen Leptospira interrogans

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