Inactivation of the fliY gene encoding a flagellar motor switch protein attenuates mobility and virulence of Leptospira interrogansstrain Lai

Liao, Shunbao; Sun, Aijun; Ojcius, David M.; Wu, Shuiqing; Zhao, Jun; Yan, Jie

doi:10.1186/1471-2180-9-253

Cited by 89 publications

(71 citation statements)

References 58 publications

(71 reference statements)

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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: Discussionsupporting

confidence: 77%

“…The bacteria are highly motile, and previous studies have demonstrated that both full motility (11,12) and an intact LPS (13) are required for successful colonization of the host. Unlike the majority of other pathogenic Gram-negative bacteria, Leptospira genomes lack the genes encoding delivery systems, such as type III and IV secretion systems, and classical virulence proteins, such as toxins and effectors (14).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 77%

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confidence: 99%

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

et al. 2015

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“…It would be interesting to examine the roles of the other Fur homologs in L. interrogans. However, directed mutagenesis is extremely inefficient in pathogenic leptospires, with only two targeted mutations in a pathogenic species of Leptospira being reported to date (16,39). Ongoing screening of our transposon library has not yet yielded mutations of the other Fur homologs.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Response ofLeptospira interrogansto Iron Limitation and Characterization of a PerR Homolog

et al. 2010

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Leptospirosis is a globally significant zoonosis caused by Leptospira spp. Iron is essential for growth of most bacterial species. Since iron availability is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In many bacteria, expression of iron uptake and storage proteins is regulated by Fur. L. interrogans encodes four predicted Fur homologs; we have constructed a mutation in one of these, la1857. We conducted microarray analysis to identify iron-responsive genes and to study the effects of la1857 mutation on gene expression. Under iron-limiting conditions, 43 genes were upregulated and 49 genes were downregulated in the wild type. Genes encoding proteins with predicted involvement in inorganic ion transport and metabolism (including TonB-dependent proteins and outer membrane transport proteins) were overrepresented in the upregulated list, while 54% of differentially expressed genes had no known function. There were 16 upregulated genes of unknown function which are absent from the saprophyte L. biflexa and which therefore may encode virulence-associated factors. Expression of iron-responsive genes was not significantly affected by mutagenesis of la1857, indicating that LA1857 is not a global regulator of iron homeostasis. Upregulation of heme biosynthetic genes and a putative catalase in the mutant suggested that LA1857 is more similar to PerR, a regulator of the oxidative stress response. Indeed, the la1857 mutant was more resistant to peroxide stress than the wild type. Our results provide insights into the role of iron in leptospiral metabolism and regulation of the oxidative stress response, including genes likely to be important for virulence.

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“…These avirulent mutants were disrupted in genes of the LPS biosynthesis locus (25) and in genes encoding a heme oxygenase (26), a lipoprotein, Loa22, of unknown function (34), or the flagellar motor switch protein FliY (18). However, only the attenuation of the loa22 mutant was confirmed by complementation studies (34).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of clpB in the Pathogen Leptospira interrogans Reduces Virulence and Resistance to Stress Conditions

et al. 2011

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Leptospira interrogans is the causative agent of leptospirosis, which is an emerging zoonotic disease. Resistance to stress conditions is largely uncharacterized for this bacterium. We therefore decided to analyze a clpB mutant that we obtained by random transposon mutagenesis. The mutant did not produce any of the two isoforms of ClpB. The clpB mutant exhibited growth defects at 30°and 37°C and in poor nutrient medium and showed increased susceptibility to oxidative stress, whereas the genetically complemented strain was restored in ClpB expression and in vitro wild-type growth. We also showed that the clpB mutant was attenuated in virulence in an animal model of acute leptospirosis. Our findings demonstrate that ClpB is involved in the general stress response. The chaperone is also necessary, either directly or indirectly, for the virulence of the pathogen L. interrogans.

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Inactivation of the fliY gene encoding a flagellar motor switch protein attenuates mobility and virulence of Leptospira interrogansstrain Lai

Cited by 89 publications

References 58 publications

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

Transcriptional Response ofLeptospira interrogansto Iron Limitation and Characterization of a PerR Homolog

Inactivation of clpB in the Pathogen Leptospira interrogans Reduces Virulence and Resistance to Stress Conditions

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