DUAL FUNCTION OF PNEUMOLYSIN IN THE EARLY PATHOGENESIS OF MURINE PNEUMOCOCCAL PNEUMONIA

Streptococcus pneumoniae is one of the most common etiologic agents of community-acquired pneumonia, particularly bacteremic pneumonia. Pneu molysin, a multifunctional cytotoxin, is a putative virulence factor f or S. pneumoniae; however, a direct role for pneumolysin in the early pathogenesis of pneumococcal pneumonia has not been confirmed in vivo. We compared the growth of a pneumolysin-deficient (PLY[-]) type 2 S. pneumoniae strain with its isogenic wild-type strain (PLY[+]) after di rect endotracheal instillation of bacteria into murine lungs. Compared with PLY(-) bacteria, infection with PLY(+) bacteria produced greater injury to the alveolar-capillary barrier, as assayed by albumin conce ntrations in alveolar lavage, and substantially greater numbers of PLY (+) bacteria were recovered in alveolar lavages and lung homogenates a t 3 and 6 h after infection. The presence of pneumolysin also contribu ted to the development of bacteremia, which was detected at 3 h after intratracheal instillation of PLY(+) bacteria. The direct effects of p neumolysin on lung injury and on the ability of pneumococci to evade l ocal lung defenses was confirmed by addition of purified recombinant p neumolysin to inocula of PLY(-) pneumococci, which promoted growth of PLY(-) bacteria in the lung to levels comparable to those seen with th e PLY(+) strain, We further demonstrated the contributions of both the cytolytic and the complement-activating properties of pneumolysin on enhanced bacterial growth in murine lungs using genetically modified p neumolysin congeners and genetically complement-deficient mice. Thus, pneumolysin facilitates intraalveolar replication of pneumococci, pene tration of bacteria from alveoli into the interstitium of the lung, an d dissemination of pneumococci into the bloodstream during experimenta l pneumonia. Moreover, both the cytotoxic and the complement-activatin g activities of pneumolysin may contribute independently to the acute pulmonary injury and the high rates of bacteremia which characterize p neumococcal pneumonia.