Anchorless adhesins and invasins of Gram-positive bacteria: a new class of virulence factors

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Response from JenkinsonIt is well established that Gram-positive bacteria that colonize humans express a multiplicity of cell-surface proteins with adhesive properties. These adhesins equip the bacteria with a complement of binding functions that facilitate their growth and survival at different host sites, according to receptor availabilities, microbial competition or immune challenges. Thus, it can be envisaged that a repertoire of adhesins recognizing a range of host receptors would be beneficial for streptococcal colonization of complex macromolecular environments, such as saliva-coated surfaces or tissues within the oral cavity [1xStreptococcal adhesion and colonization. Jenkinson, H.F and Lamont, R.J. Crit. Rev. Oral Biol. Med. 1997; 8: 175–200Crossref | PubMedSee all References][1]. However, it is more difficult to reconcile why strains of Streptococcus pyogenes (group A streptococci, GAS), which colonize the throat, nasopharynx or skin, express various repertoires of at least eight secreted proteins that bind the same host molecule, fibronectin [2.xIdentification and characterization of a novel fibronectin-binding protein on the surface of group A streptococci. Rocha, C.L and Fischetti, V.A. Infect. Immun. 1999; 67: 2720–2728PubMedSee all References, 3.xFba, a novel fibronectin-binding protein from Streptococcus pyogenes, promotes bacterial entry into epithelial cells, and the fba gene is positively transcribed under the Mga regulator. Terao, Y et al. Mol. Microbiol. 2001; 42: 75–86Crossref | PubMed | Scopus (115)See all References]. Although several of these proteins assist in mediating bacterial adhesion to fibronectin or to epithelial cells in vitro, it is clear that some, including serum opacity factor (SOF) [4xSerum opacity factor is a major fibronectin-binding protein and a virulence determinant of M type 2 Streptococcus pyogenes. Courtney, H.S et al. Mol. Microbiol. 1999; 32: 89–98Crossref | PubMedSee all References][4] and Fba (in SOF− strains) [3xFba, a novel fibronectin-binding protein from Streptococcus pyogenes, promotes bacterial entry into epithelial cells, and the fba gene is positively transcribed under the Mga regulator. Terao, Y et al. Mol. Microbiol. 2001; 42: 75–86Crossref | PubMed | Scopus (115)See all References][3], also contribute directly to the pathogenesis of GAS infections in vivo. Thus fibronectin-binding proteins not only mediate bacterial adhesion but they also modulate eukaryotic cell functions and the susceptibility of the host to invasive disease.We have recently shown that PavA, the first fibronectin-binding protein to be described in S. pneumoniae, is essential for pneumococcal virulence [5xThe pavA gene of Streptococcus pneumoniae encodes a fibronectin-binding protein that is essential for virulence. Holmes, A.R et al. Mol. Microbiol. 2001; 41: 1395–1408Crossref | PubMed | Scopus (134)See all References][5]. PavA (62 kDa) is a cell-surface-associated polypeptide but the mechanisms by which it is secreted and retained at the cell surface are unknown. Isogenic mutants of S. pneumoniae abrogated in production of PavA, or producing a 45-kDa carboxy-terminally truncated protein, are only partially reduced in their abilities to bind fibronectin, but are essentially avirulent. These observations fit with the notion that PavA, like some GAS fibronectin-binding proteins, has a distinct and crucial virulence-related function in addition to its ability to mediate bacterial adhesion to fibronectin. Thus it can be proposed that fibronectin-binding regions simply act as eukaryotic host cell targeting sequences. In the case of PavA, retention or reassociation of the protein at the pneumococcal cell surface would ensure delivery of PavA virulence function(s) at the interface of pneumococcus and host.Although our isogenic mutant data are unequivocal in demonstrating that expression of PavA is essential for pneumococcal virulence [5xThe pavA gene of Streptococcus pneumoniae encodes a fibronectin-binding protein that is essential for virulence. Holmes, A.R et al. Mol. Microbiol. 2001; 41: 1395–1408Crossref | PubMed | Scopus (134)See all References][5], it is not possible to rule out that pavA mutations might have pleiotropic effects on expression or activities of other factors necessary for pneumococcal growth and survival in vivo. Indeed, this is a potential problem for all assignments of gene functions based upon the phenotypic properties of perfect isogenic mutants. Future analyses of isogenic mutants will be assisted by the use of proteomics or DNA microarrays to catalogue their protein- or gene-expression profiles. This will lead to better understanding of how virulence gene functions are integrated within metabolic pathway networks and globally regulated systems.