Cpa, the Outer Membrane Protease of<i>Cronobacter sakazakii</i>, Activates Plasminogen and Mediates Resistance to Serum Bactericidal Activity

Franco, Augusto A.; Kothary, Mahendra H.; Gopinath, Gopal; Jarvis, Karen G.; Grim, Chris; Hu, Lan; Datta, Atin R.; McCardell, Barbara A.; Tall, Ben D.

doi:10.1128/iai.01165-10

Cited by 70 publications

(69 citation statements)

References 61 publications

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“…83 In Cronobacter, Franco et al 78 reported that plasmid pESA3 contain 2 clusters of genes, a homolog of an ABC transport-mediated iron uptake siderophore system (eitCBAD operon) and a siderophoremediated iron acquisition system (iucABCD/iutA operon). This characteristic may contribute to the systemic survival of C. sakazakii and subsequent invasion of the CNS to cause diseases.…”

Section: Iron Acquisition Gene Systemmentioning

confidence: 99%

“…76 Franco et al and Cruz et al also portray the prevalence and distribution of plasmid-encoded virulence genes cpa, a type 6 secretion system (T6SS, also encoded on pESA3) and a filamentous haemaggltunin/adhesion (FHA) gene locus (located on pCTU1) among 231 Cronobacter strains. 77,78 Sialic acid utilization Sialic acid is found in human milk and in infant formulae in the form of sialyloligosaccharides. 79 These oligosaccharides remain undigested in neonates and infants, therefore the intestinal microvilli of neonates have increased sialic acid and N-acetylglucosamine residues leading to proliferation of gut microbiota.…”

Section: Enterotoxinmentioning

confidence: 99%

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Insights into virulence factors determining the pathogenicity ofCronobacter sakazakii

2015

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Section: Iron Acquisition Gene Systemmentioning

confidence: 99%

Section: Enterotoxinmentioning

confidence: 99%

Insights into virulence factors determining the pathogenicity ofCronobacter sakazakii

2015

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“…Studies have shown that C. sakazakii can invade and translocate efficiently across cultured human intestinal epithelial cells, as well as endothelial cells, experimentally mimicking the potential path of meningitis (14,16). A plasmid-borne outer membrane protease (Cpa) is reported to be involved in C. sakazakii protection against complement-dependent serum killing and efficient invasion by activating plasminogen into plasmin (17). Furthermore, plasmidborne iron acquisition systems, such as an aerobacterin-like siderophore (cronobactin) and an ABC ferric-iron transporter (eit-ABCE), might enable Cronobacter spp.…”

mentioning

confidence: 99%

hfq Plays Important Roles in Virulence and Stress Adaptation in Cronobacter sakazakii ATCC 29544

et al. 2015

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cCronobacter spp. are opportunistic pathogens that cause neonatal meningitis and sepsis with high mortality in neonates. Despite the peril associated with Cronobacter infection, the mechanisms of pathogenesis are still being unraveled. Hfq, which is known as an RNA chaperone, participates in the interaction with bacterial small RNAs (sRNAs) to regulate posttranscriptionally the expression of various genes. Recent studies have demonstrated that Hfq contributes to the pathogenesis of numerous species of bacteria, and its roles are varied between bacterial species. Here, we tried to elucidate the role of Hfq in C. sakazakii virulence. In the absence of hfq, C. sakazakii was highly attenuated in dissemination in vivo, showed defects in invasion (3-fold) into animal cells and survival (10 3 -fold) within host cells, and exhibited low resistance to hydrogen peroxide (10 2 -fold). Remarkably, the loss of hfq led to hypermotility on soft agar, which is contrary to what has been observed in other pathogenic bacteria. The hyperflagellated bacteria were likely to be attributable to the increased transcription of genes associated with flagellar biosynthesis in a strain lacking hfq. Together, these data strongly suggest that hfq plays important roles in the virulence of C. sakazakii by participating in the regulation of multiple genes.

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“…Omptins are outer membrane (OM) proteases commonly found in Gram-negative pathogens. They play important roles at the host-pathogen interface by processing or degrading a variety of host and bacterial proteins (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Many omptins are found among pathogens of the Enterobacteriaceae family (11).…”

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confidence: 99%

Antimicrobial Peptide Conformation as a Structural Determinant of Omptin Protease Specificity

et al. 2015

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Bacterial proteases contribute to virulence by cleaving host or bacterial proteins to promote survival and dissemination. Omptins are a family of proteases embedded in the outer membrane of Gram-negative bacteria that cleave various substrates, including host antimicrobial peptides, with a preference for cleaving at dibasic motifs. OmpT, the enterohemorrhagic Escherichia coli (EHEC) omptin, cleaves and inactivates the human cathelicidin LL-37. Similarly, the omptin CroP, found in the murine pathogen Citrobacter rodentium, which is used as a surrogate model to study human-restricted EHEC, cleaves the murine cathelicidin-related antimicrobial peptide (CRAMP). Here, we compared the abilities of OmpT and CroP to cleave LL-37 and CRAMP. EHEC OmpT degraded LL-37 and CRAMP at similar rates. In contrast, C. rodentium CroP cleaved CRAMP more rapidly than LL-37. The different cleavage rates of LL-37 and CRAMP were independent of the bacterial background and substrate sequence specificity, as OmpT and CroP have the same preference for cleaving at dibasic sites. Importantly, LL-37 was ␣-helical and CRAMP was unstructured under our experimental conditions. By altering the ␣-helicity of LL-37 and CRAMP, we found that decreasing LL-37 ␣-helicity increased its rate of cleavage by CroP. Conversely, increasing CRAMP ␣-helicity decreased its cleavage rate. This structural basis for CroP substrate specificity highlights differences between the closely related omptins of C. rodentium and E. coli. In agreement with previous studies, this difference in CroP and OmpT substrate specificity suggests that omptins evolved in response to the substrates present in their host microenvironments. IMPORTANCEOmptins are recognized as key virulence factors for various Gram-negative pathogens. Their localization to the outer membrane, their active site facing the extracellular environment, and their unique catalytic mechanism make them attractive targets for novel therapeutic strategies. Gaining insights into similarities and variations between the different omptin active sites and subsequent substrate specificities will be critical to develop inhibitors that can target multiple omptins. Here, we describe subtle differences between the substrate specificities of two closely related omptins, CroP and OmpT. This is the first reported example of substrate conformation acting as a structural determinant for omptin activity between OmpT-like proteases. Bacterial proteases are key virulence factors involved in hostpathogen interactions. Omptins are outer membrane (OM) proteases commonly found in Gram-negative pathogens. They play important roles at the host-pathogen interface by processing or degrading a variety of host and bacterial proteins (1-10). Many omptins are found among pathogens of the Enterobacteriaceae family (11). The prototypical omptins are Escherichia coli OmpT and Yersinia pestis Pla, which inactivate antimicrobial peptides (AMPs) and activate plasminogen into plasmin, respectively (4, 6). Omptins are ␤-barrel proteases embedded ...

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Cpa, the Outer Membrane Protease ofCronobacter sakazakii, Activates Plasminogen and Mediates Resistance to Serum Bactericidal Activity

Cited by 70 publications

References 61 publications

Insights into virulence factors determining the pathogenicity ofCronobacter sakazakii

Insights into virulence factors determining the pathogenicity ofCronobacter sakazakii

hfq Plays Important Roles in Virulence and Stress Adaptation in Cronobacter sakazakii ATCC 29544

Antimicrobial Peptide Conformation as a Structural Determinant of Omptin Protease Specificity

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