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Pili prove pertinent to enterococcal endocarditis
Jonathan M. Budzik and Olaf Schneewind
Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
Address correspondence to: Olaf Schneewind, 920 East 58th Street, Cummings Life Sciences Center Room 607b, Chicago, Illinois 60637, USA. Phone: (773) 834-9060; Fax: (773) 834-8150; E-mail: oschnee@bsd.uchicago.edu.
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Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
Address correspondence to: Olaf Schneewind, 920 East 58th Street, Cummings Life Sciences Center Room 607b, Chicago, Illinois 60637, USA. Phone: (773) 834-9060; Fax: (773) 834-8150; E-mail: oschnee@bsd.uchicago.edu.
Find articles by Schneewind, O. in: JCI | PubMed | Google Scholar
Published October 2, 2006 - More info
J Clin Invest. 2006;116(10):2582–2584. https://doi.org/10.1172/JCI30088.
© 2006 The American Society for Clinical Investigation
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Abstract
Increasing multidrug resistance in Enterococcus faecalis, a nosocomial opportunist and common cause of bacterial endocarditis, emphasizes the need for alternative therapeutic approaches such as immunotherapy or immunoprophylaxis. In an earlier study, we demonstrated the presence of antibodies in E. faecalis endocarditis patient sera to recombinant forms of 9 E. faecalis cell wall–anchored proteins; of these, we have now characterized an in vivo–expressed locus of 3 genes and an associated sortase gene (encoding sortase C; SrtC). Here, using mutation analyses and complementation, we demonstrated that both the ebp (encoding endocarditis and biofilm-associated pili) operon and srtC are important for biofilm production of E. faecalis strain OG1RF. In addition, immunogold electron microscopy using antisera against EbpA–EbpC proteins as well as patient serum demonstrated that E. faecalis produces pleomorphic surface pili. Assembly of pili and their cell wall attachment appeared to occur via a mechanism of cross-linking of the Ebp proteins by the designated SrtC. Importantly, a nonpiliated, allelic replacement mutant was significantly attenuated in an endocarditis model. These biologically important surface pili, which are antigenic in humans during endocarditis and encoded by a ubiquitous E. faecalis operon, may be a useful immunotarget for studies aimed at prevention and/or treatment of this pathogen.
Authors
Sreedhar R. Nallapareddy, Kavindra V. Singh, Jouko Sillanpää, Danielle A. Garsin, Magnus Höök, Stanley L. Erlandsen, Barbara E. Murray
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Enterococcus faecalis — snapshots of the pathogen
Enterococcus faecalis, a commensal bacterium of human biliary and gastrointestinal tracts, is a leading cause of surgical site, bloodstream, and urinary tract infections (1). Furthermore, E. faecalis is also a causal agent of bacterial endocarditis, whose complications — including congestive heart failure, septic emboli, and glomerulonephritis —result in mortality (2). Current management of enterococcal endocarditis involves administration of a combination of antimicrobials; however, the emergence of strains with multiple antibiotic resistance, including vancomycin resistance (e.g., vancomycin-resistant enterococci), present continuously increasing problems (3). Epidemiological studies show that more than 20% of enterococci isolated from infections of intensive care unit patients display vancomycin resistance (4). Thus, research that has the potential to unveil new therapies or preventive measures that disrupt the pathogenesis of enterococcal endocarditis is urgently needed.
What makes E. faecalis a pathogen? Unlike group A streptococci or Staphylococcus aureus, which are virulent microbes that secrete a plethora of hemolysins and toxins to battle innate immune responses (5, 6), E. faecalis pathogenesis relies on fewer virulence factors (7). Two protein adhesins, enterococcal surface protein (Esp) and adhesion to collagen from E. faecalis (Ace), are thought to mediate enterococcal attachment to host tissues (8, 9), while aggregation substance (AS) promotes aggregation of replicating microbes (10). Enterococci regulate protease expression (a secreted virulence factor involved in tissue degradation) via the E. faecalis regulator (fsr) quorum-sensing locus, including fsrC sensory kinase, fsrA response regulator, and fsrB-derived autoinducer (11). Once an infectious nidus harbors threshold numbers of enterococci, Fsr signaling activates protease secretion (11). Esp, Ace, Fsr, and protease are involved in the formation of a biofilm, a surface-attached bacterial community enclosed in extracellular matrix where enterococci assume a slower growth rate, increased antibiotic resistance, and elevated frequency of lateral gene transfer (11). Finally, cytolysin, a toxin secreted by enterococci, derives its cytolytic activity from 2 peptides that possess modifications characteristic of lantibiotics (compounds with thioether amino acids that are derived by posttranslational modification from ribosomally synthesized precursors) (12, 13). Together these peptides lyse different host cells including polymorphonuclear leukocytes, a critical immune defense against E. faecalis infection (Figure 1) (14).
Figure 1Role for pili in the establishment of E. faecalis infection. Enterococci may use pili (surface fibrils) for microbial attachment to host tissues (i). Surface proteins (e.g., AS, Esp, and Ace) are involved in establishing tight bacterial adherence to host cells (ii). Enterococcal aggregation induces biofilm formation (iii) and elaboration of exopolysaccharide matrix (blue surface layer). Quorum-sensing–controlled expression of protease and cytolysin mediate host cell death and spread of infection (iv). Schematic modified with permission from ASM Press (1).
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