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Establishment of a young mouse model and identification of an allelic variation of zmpB in complicated pneumonia caused by Streptococcus pneumoniae*

Objective:Complicated pneumonia, including necrotizing pneumonia, lung abscess, and empyema, caused by Streptococcus pneumoniae in children has been increasing. We thus determined to investigate its virulence in an animal model and to identify virulence factors of S. pneumoniae. Design:Prospective, randomized, controlled animal study. Setting:University medical laboratory. Subjects:Male Balb/c-strain mice, 3 wks old. Interventions:We used a young mouse model to monitor bacterial virulence and a microarray to compare gene expression between S. pneumoniae from children with complicated and noncomplicated pneumonia. Deletion and complementation of a candidate gene were performed to study its role on the virulence of S. pneumoniae. Measurements and Main Results:A model of complicated pneumonia in young mice infected with strains of S. pneumoniae from children with complicated pneumonia was established. Using a microarray analysis, differences in zinc metalloprotease B (zmpB) RNA hybridization between two strains from children with complicated pneumonia (NTUH-p28 and NTUH-p15) and a strain (NTUH-p3) from a child with pneumococcal lobar pneumonia were found. Confirmatory assays revealed the signal differences were due to sequence variation in the zmpB gene. Infection with the zmpB deletion mutant of NTUH-p15 showed a significant decrease in the severity of pneumonia and no destructive lung injury. The zmpB complementation strain of NTUH-p15 significantly restored the level of inflammation and caused lung necrosis. For studying the effect of allelic variation of zmpB on the virulence of S. pneumoniae, we added zmpB of NTUH-p15 in the zmpB deletion mutant of NTUH-p3, which resulted in a higher bacterial burden than that in wild-type NTUH-p3. Conclusions:A young mouse model is established for complicated pneumococcal pneumonia. This model proved that allelic variation of zmpB affects the virulence of S. pneumoniae.