Leucine-Responsive Regulatory Protein (Lrp) Acts as a Virulence Repressor in<i>Salmonella enterica</i>Serovar Typhimurium

Baek, Chang Ho; Wang, Shifeng; Roland, Kenneth L.; Curtiss, Roy

doi:10.1128/jb.01142-08

Cited by 58 publications

(72 citation statements)

References 93 publications

(95 reference statements)

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“…The effects seen on hilA and ssrA expression are independent of the presence of leucine (312). In contrast, invF repression does require leucine, whereas expression of the spvABCD genes, which is prevented by Lrp protection of the transcriptional start site of the spvA gene, is antagonized by leucine (302,312).…”

Section: Other Regulatorsmentioning

confidence: 76%

“…Lrp constitutive expression dramatically attenuates virulence, leading to defects in invasion, cytotoxicity, and colonization, whereas lrp deletion enhances these activities. Particularly, Lrp represses transcription of the hilA, invF (SPI-1), ssrA (SPI-2), and spvA (pSLT plasmid) genes by direct binding to a consensus DNA motif (302,312). The effects seen on hilA and ssrA expression are independent of the presence of leucine (312).…”

Section: Other Regulatorsmentioning

confidence: 85%

“…Particularly, Lrp represses transcription of the hilA, invF (SPI-1), ssrA (SPI-2), and spvA (pSLT plasmid) genes by direct binding to a consensus DNA motif (302,312). The effects seen on hilA and ssrA expression are independent of the presence of leucine (312). In contrast, invF repression does require leucine, whereas expression of the spvABCD genes, which is prevented by Lrp protection of the transcriptional start site of the spvA gene, is antagonized by leucine (302,312).…”

Section: Other Regulatorsmentioning

confidence: 99%

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Salmonella enterica Serovar Typhimurium Skills To Succeed in the Host: Virulence and Regulation

2013

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SUMMARY Salmonella enterica serovar Typhimurium is a primary enteric pathogen infecting both humans and animals. Infection begins with the ingestion of contaminated food or water so that salmonellae reach the intestinal epithelium and trigger gastrointestinal disease. In some patients the infection spreads upon invasion of the intestinal epithelium, internalization within phagocytes, and subsequent dissemination. In that case, antimicrobial therapy, based on fluoroquinolones and expanded-spectrum cephalosporins as the current drugs of choice, is indicated. To accomplish the pathogenic process, the Salmonella chromosome comprises several virulence mechanisms. The most important virulence genes are those located within the so-called Salmonella pathogenicity islands (SPIs). Thus far, five SPIs have been reported to have a major contribution to pathogenesis. Nonetheless, further virulence traits, such as the pSLT virulence plasmid, adhesins, flagella, and biofilm-related proteins, also contribute to success within the host. Several regulatory mechanisms which synchronize all these elements in order to guarantee bacterial survival have been described. These mechanisms govern the transitions from the different pathogenic stages and drive the pathogen to achieve maximal efficiency inside the host. This review focuses primarily on the virulence armamentarium of this pathogen and the extremely complicated regulatory network controlling its success.

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Section: Other Regulatorsmentioning

confidence: 76%

Section: Other Regulatorsmentioning

confidence: 85%

Section: Other Regulatorsmentioning

confidence: 99%

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Salmonella enterica Serovar Typhimurium Skills To Succeed in the Host: Virulence and Regulation

2013

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“…The term "hypervirulent" is often used to describe a strain that exhibits a significant increase in virulence compared to either the parental wild-type strain or related strains within the same species. Such an increase in virulence may be due to the functional loss of one or more genes, and this phenomenon has been documented in wild-type strains or discovered through genetic manipulation of strains within the laboratory (3,26,44). However, such genes are still functional in either the majority of wild-type strains within the same species or, in the case of labinduced hypervirulence, in the parent wild-type strain and therefore do not fit our criteria for AVGs.…”

Section: What Is (And What Is Not) An Avgmentioning

confidence: 94%

Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss

2012

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The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation-a "fine-tuning" process-for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens.

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“…Lrp has also been shown to regulate a variety of virulence-associated genes in many other pathogens (2,19,24,29,32,60). Although Lrp is essential for virulence in Xenorhabdus nematophila (15,29), it appears to act as a virulence repressor in Salmonella enterica subtype Typhimurium (2).…”

Section: Discussionmentioning

confidence: 99%

Branched-Chain Amino Acids Are Required for the Survival and Virulence ofActinobacillus pleuropneumoniaein Swine

et al. 2009

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In Actinobacillus pleuropneumoniae, which causes porcine pleuropneumonia, ilvI was identified as an in vivo-induced (ivi) gene and encodes the enzyme acetohydroxyacid synthase (AHAS) required for branchedchain amino acid (BCAA) biosynthesis. ilvI and 7 of 32 additional ivi promoters were upregulated in vitro when grown in chemically defined medium (CDM) lacking BCAA. Based on these observations, we hypothesized that BCAA would be found at limiting concentrations in pulmonary secretions and that A. pleuropneumoniae mutants unable to synthesize BCAA would be attenuated in a porcine infection model. Quantitation of free amino acids in porcine pulmonary epithelial lining fluid showed concentrations of BCAA ranging from 8 to 30 mol/liter, which is 10 to 17% of the concentration in plasma. The expression of both ilvI and lrp, a global regulator that is required for ilvI expression, was strongly upregulated in CDM containing concentrations of BCAA similar to those found in pulmonary secretions. Deletion-disruption mutants of ilvI and lrp were both auxotrophic for BCAA in CDM and attenuated compared to wild-type A. pleuropneumoniae in competitive index experiments in a pig infection model. Wild-type A. pleuropneumoniae grew in CDM؉BCAA but not in CDM؊BCAA in the presence of sulfonylurea AHAS inhibitors. These results clearly demonstrate that BCAA availability is limited in the lungs and support the hypothesis that A. pleuropneumoniae, and potentially other pulmonary pathogens, uses limitation of BCAA as a cue to regulate the expression of genes required for survival and virulence. These results further suggest a potential role for AHAS inhibitors as antimicrobial agents against pulmonary pathogens.Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, a disease of significant economic importance throughout the swine-raising areas of the world (6, 48). This pathogen possesses several well-studied virulence factors, including Apx toxins (20), capsular polysaccharides (57, 58), lipopolysaccharide (1, 17, 41), fimbriae (63), and ironscavenging proteins (13, 50), which aid in the pathogenesis of acute pleuropneumonia marked by edema, hemorrhage, and necrosis (6, 26). In a search for additional virulence factors of this pathogen, we developed an in vivo expression technology (IVET) system and used this genetic tool to identify A. pleuropneumoniae gene promoters that are upregulated in vivo in the swine lung during infection compared to growth on laboratory media (22, 55).One of the A. pleuropneumoniae in vivo-induced (ivi) promoters that we identified drives the ilvIH operon, which encodes both large and small subunits of acetohydroxy acid synthase isozyme III (AHAS) (55). AHAS enzymes catalyze pivotal steps in the biosynthesis of the branched-chain amino acids (BCAA) isoleucine, leucine, and valine (31). In a survey of IVET, signature-tagged mutagenesis, and microarray studies of other pathogens, we observed that genes involved in BCAA biosynthesis were frequently identified in studies of pathogen...

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Leucine-Responsive Regulatory Protein (Lrp) Acts as a Virulence Repressor inSalmonella entericaSerovar Typhimurium

Cited by 58 publications

References 93 publications

Salmonella enterica Serovar Typhimurium Skills To Succeed in the Host: Virulence and Regulation

Salmonella enterica Serovar Typhimurium Skills To Succeed in the Host: Virulence and Regulation

Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss

Branched-Chain Amino Acids Are Required for the Survival and Virulence ofActinobacillus pleuropneumoniaein Swine

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