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Background
Calcineurin (CaN) is an important serine-threonine phosphatase (PP2B), which plays a crucial role in calcium-calmodulin mediated signal transduction events. Calcineurin has been implicated in pathogenesis of various diseases cardiac hypertrophy, diabetic neuropathy and Alzheimer's, however its role in neoplasia remains unclear. 相似文献22.
Gordon Y. C. Cheung Dorothee Kretschmer Anthony C. Duong Anthony J. Yeh Trung V. Ho Yan Chen Hwang-Soo Joo Barry N. Kreiswirth Andreas Peschel Michael Otto 《PLoS pathogens》2014,10(8)
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms. 相似文献
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The phenol-soluble modulin PSM-mec is the only known staphylococcal toxin that is encoded on a mobile antibiotic resistance determinant, namely the staphylococcal cassette chromosome (SCC) element mec encoding resistance to methicillin. Here we show that the psm-mec gene is found frequently among methicillin-resistant Staphylococcus aureus (MRSA) strains of SCCmec types II, III, and VIII, and is a conserved part of the class A mec gene complex. Controlled expression of AgrA versus RNAIII in agr mutants of all 3 psm-mec-positive SCCmec types demonstrated that expression of psm-mec, which is highly variable, is controlled by AgrA in an RNAIII-independent manner. Furthermore, psm-mec isogenic deletion mutants showed only minor changes in PSMα peptide production and unchanged (or, as previously described, diminished) virulence compared to the corresponding wild-type strains in a mouse model of skin infection. This indicates that the recently reported regulatory impact of the psm-mec locus on MRSA virulence, which is opposite to that of the PSM-mec peptide and likely mediated by a regulatory RNA, is minor when analyzed in the original strain background. Our study gives new insight in the distribution, regulation, and role in virulence of the PSM-mec peptide and the psm-mec gene locus. 相似文献
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Gene acquisition at the insertion site for SCCmec, the genomic island conferring methicillin resistance in Staphylococcus aureus 总被引:1,自引:0,他引:1
Staphylococcus aureus becomes resistant to methicillin by acquiring a genomic island, known as staphylococcal chromosome cassette mec (SCCmec), which contains the methicillin resistance determinant, mecA. SCCmec is site-specifically integrated into the staphylococcal chromosome at a locus known as the SCCmec attachment site (attB). In an effort to gain a better understanding of the potential that methicillin-sensitive S. aureus (MSSA) isolates have for acquiring SCCmec, the nucleotide sequences of attB and surrounding DNA regions were examined in a diverse collection of 42 MSSA isolates. The chromosomal region surrounding attB varied among the isolates studied and appears to be a common insertion point for acquired foreign DNA. Insertions of up to 15.1 kb were found containing open reading frames with homology to enterotoxin genes, restriction-modification systems, transposases, and several sequences that have not been previously described in staphylococci. Two groups, containing eight and four isolates, had sequences found in known SCCmec elements, suggesting SCCmec elements may have evolved through repeated DNA insertions at this locus. In addition, the attB sequences of the majority of MSSA isolates in this collection differ from the attB sequences of strains for which integrase-mediated SCCmec insertion or excision has been demonstrated, suggesting that some S. aureus isolates may lack the ability to site-specifically integrate SCCmec into their chromosomes. 相似文献
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Cryptic α-toxin gene in toxic shock syndrome and septicaemia strains of Staphylococcus aureus 总被引:1,自引:0,他引:1
The majority of clinical isolates of Staphylococcus aureus that produce toxic shock syndrome toxin-1 (TSST-1) fail to express alpha-toxin, despite having a copy of the hla gene in the chromosome. The hla gene was cloned from an Hla- TSST-1+ strain, Todd 555, which had been isolated from a case of toxic shock syndrome in the USA. Of the 630 bases of the Todd 555 gene sequenced, 46 differed from the hla gene sequence of strain Wood 46. The defect in alpha-toxin expression was shown to be due to a nonsense mutation which converted a CAG glutamine codon in the equivalent position in the functional Wood 46 sequence to a TAG stop codon. The same mutation was present in the hla gene cloned from a human septicaemia strain (V37) isolated in Dublin. The nonsense mutation of Todd 555 was suppressed by the supE44 mutation in Escherichia coli resulting in haemolytic activity in cell lysates. Hybrid hla genes were formed by splicing fragments of hla from Todd 555 and Wood 46. Expression of one such chimaeric hla gene in S. aureus demonstrated that the Todd 555 hla gene has a functional agr-regulated promoter. The silent hla gene may be a cryptic gene in S. aureus. 相似文献
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Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus 总被引:1,自引:0,他引:1
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