Chapter 8 : Enterococcal Virulence

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Studies of the pathogenesis of enterococcal infection are beginning to identify specific enterococcal and host traits that contribute to the balanced commensal relationship, as well as those that undermine it. This chapter provides an overview of the commensal-pathogen dynamic and the factors that influence this relationship, resulting in human infection. Factors that contribute to host specificity to which enterococci may be adapted may include species-specific mucin characteristics, coresident gastrointestinal (GI) tract flora composition, diet, and motility rates. The introduction and widespread use of antibiotics correlate with increased recognition of the problem of enterococcal infection. Early descriptions of enterococcal infection noted the wide range of conditions compatible with growth and the particular resistance to desiccation. Enterococci are "facultative" parasites, and healthy humans or animals only rarely become infected with enterococci. Because of the increasing difficulty in treating enterococcal infection, more and more effort are being devoted to understanding factors that undermine the commensal relationship, with a view toward targeting these factors with new therapeutics. In summary, the enhancement of enterococcal virulence by aggregation substance appears to occur at multiple levels. Pathogenesis studies show that aggregation substance and the cytolysin act synergistically to enhance virulence by facilitating achievement of a quorum and activating the quorum-sensing mode of cytolysin regulation, resulting in tissue damage and potentially deeper tissue invasion.

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8

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Two-Component Signal Transduction Systems
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Figure 1

The cytolysin structural subunits, designated CylL and CylL, are ribosomally synthesized in an initial precursor form and then post-translationally modified by the gene product ( ). Following modification, both subunits are secreted across the cytoplasmic membrane by the product of the next gene in the 3′ direction, , which encodes an ATP-binding cassette transporter ( ). In addition to the C-terminal ATP-binding domain common to all other ATP-binding transport systems ( ), CylB possesses a cysteine protease domain at the N terminus ( ), which upon secretion appears to remove 24- and 36-amino-acid leader sequences from CylL and CylL, respectively, generating CylL′ and CylL′ ( ). Following trimming and secretion by the CylB transporter, six amino acids in the conserved extension in each subunit are removed extracellularly by CylA, a subtilisin-like serine protease that is encoded by the gene immediately 3′ to ( ). Cleavage of the six amino acids from both CylL′ and CylL′ generates the active toxin subunits, CylL″ and CylL″ ( ). Immediately 3′ to is an ORF of 327 amino acids that is necessary and sufficient to confer immunity to sensitive strains of . This cytolysin immunity gene has been designated ( ). Recently, CylL has been shown to possess signaling activity that results in the autoinduction of the cytolysin operon by a novel quorum-sensing mechanism ( ). Autoinduction of cytolysin expression recently has been shown to involve the products of two additional ORFs encoded 5′ to the cytolysin structural genes and divergently transcribed. These ORFs have been designated and , and both function in an as yet uncharacterized manner to effect repression of the operon at subthreshold levels of the autoinducer, CylL.

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Image of Figure 2
Figure 2

Structural organization of the locus of and the locus of .

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Image of Figure 3
Figure 3

A schematic diagram representing the proposed mechanism of activation and its effect on gelatinase and serine protease synthesis. This figure is adopted from the mechanism proposed by Balaban and Novick ( ). In this model the secreted GBAP, which is an 11-amino-acid C-terminal product of , is proposed to interact with the signal transducer, FsrC, which then phosphorylates the response regulator, FsrA. The Fsr products then autoregulate their genes in a cell density-dependent manner and positively regulate expression of gelatinase and serine proteases. The Fsr products might also regulate other virulence factors or surface proteins either directly or indirectly.

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Figure 4

Model for the synergy of the cytolysin and aggregation substance/Esp.

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Image of Figure 5
Figure 5

Structural organizations of Ace of and Cna of . Ace, diagram of Ace. S, putative signal peptide; A domain, nonrepetitive binding domain; В domain, repeat region (B domain of ace consists of 20-amino-acid partial repeat followed by two to five repeats of 47-amino-acid region); W, cell wall domain; M, membrane-spanning domain; and C, charged C-terminal region. Cna, diagram of Cna. В domain consists of two to four repeats of 187-amino-acid region. Hatched regions represent amino acids 174 to 319 of the Ace protein that corresponds to 151 to 318 amino acids of Cna (this region has been shown to be critical for collagen binding).

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Figure 6

Expression of OG1RF gene cluster in . Proteinase ?- and periodate-treated cell lysates of the cosmid clone containing cluster were probed with endocarditis patient serum on Western blot. (This figure is adapted from reference .)

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Figure 7

Organization of the locus of OG1RF. Open boxes represent ORFs and arrows above the boxes show direction of transcription. Presumed transcripts are shown by a dashed line, and the transcripts supported by experimental data are delineated with a bold line. The sites of disruptions in the constructed and mutants of OG1RF are marked with vertical arrows. Both and mutants were attenuated in a mouse peritonitis model ( ) and showed increased resistance to phagocytosis in neutrophil killing assay ( ). (This figure is adapted from reference .)

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Table 1

Correlation of in vitro binding phenotypes of nine different strains with in vitro expression of Ace

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8
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Table 2

Database homologies of the ORFs of gene cluster

Citation: Gilmore M, Coburn P, Nallapareddy S, Murray B. 2002. Enterococcal Virulence, p 301-354. In Gilmore M, Clewell D, Courvalin P, Dunny G, Murray B, Rice L (ed), The Enterococci. ASM Press, Washington, DC. doi: 10.1128/9781555817923.ch8