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However, the bacterial and host factors that provoke the progression from asymptomatic colonization to invasive disease are yet to be fully defined. In this study, we investigated the effects of single and combined mutations in genes encoding pneumolysin (Ply), pneumococcal surface protein A (PspA), and pneumococcal surface protein C (PspC, also known as choline-binding protein A) on the pathogenicity of<jats:italic>Streptococcus pneumoniae<\/jats:italic>serotype 2 (D39) in mice. Following intranasal challenge with D39, stable colonization of the nasopharynx was maintained over a 7-day period at a level of approximately 10<jats:sup>5<\/jats:sup>bacteria per mouse. The abilities of the mutant deficient in PspA to colonize the nasopharynx and to cause lung infection and bacteremia were significantly reduced. Likewise, the PspC mutant and, to a lesser extent, the Ply mutant also had reduced abilities to colonize the nasopharynx. As expected, the double mutants colonized less well than the parent to various degrees and had difficulty translocating to the lungs and blood. A significant additive attenuation was observed for the double and triple mutants in pneumonia and systemic disease models. Surprisingly, the colonization profile of the derivative lacking all three proteins was similar to that of the wild type, indicating virulence gene compensation. These findings further demonstrate that the mechanism of pneumococcal pathogenesis is highly complex and multifactorial but ascribes a role for each of these virulence proteins, alone or in combination, in the process.<\/jats:p>","DOI":"10.1128\/iai.01384-06","type":"journal-article","created":{"date-parts":[[2007,2,2]],"date-time":"2007-02-02T17:24:59Z","timestamp":1170437099000},"page":"1843-1851","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":79,"title":["Contributions of Pneumolysin, Pneumococcal Surface Protein A (PspA), and PspC to Pathogenicity of<i>Streptococcus pneumoniae<\/i>D39 in a Mouse Model"],"prefix":"10.1128","volume":"75","author":[{"given":"Abiodun D.","family":"Ogunniyi","sequence":"first","affiliation":[{"name":"School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim S.","family":"LeMessurier","sequence":"additional","affiliation":[{"name":"School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikki M. 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