Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia.

Abstract

Streptococcus pneumoniae is one of the most common etiologic agents of community-acquired pneumonia, particularly bacteremic pneumonia. Pneumolysin, a multifunctional cytotoxin, is a putative virulence factor for 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 pneumolysindeficient (PLY[ -]) type 2 S. pneumoniae strain with its isogenic wild-type strain (PLY [ + ]) after direct 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 concentrations in alveolar lavage, and substantially greater numbers of PLY( +) bacteria were recovered in alveolar lavages and lung homogenates at 3 and 6 h after infection. The presence of pneumolysin also contributed to the development of bacteremia, which was detected at 3 h after intratracheal instillation of PLY( +) bacteria.The direct effects of pneumolysin on lung injury and on the ability of pneumococci to evade local lung defenses was confirmed by addition of purified recombinant pneumolysin to inocula of PLY( -) pneumococci, which promoted growth of PLY( -) bacteria in the lung to levels comparable to those seen with the 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 pneumolysin congeners and genetically complement-deficient mice.Thus, pneumolysin facilitates intraalveolar replication of pneumococci, penetration of bacteria from alveoli into the interstitium of the lung, and dissemination of pneumococci into the bloodstream during experimental pneumonia. Moreover, both the cytotoxic and the complement-activating activities of pneumolysin may contribute independently to the acute pulmonary injury and the high rates of bacteremia which characterize pneumococcal pneumonia. (J. Clin. In-

Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis

“…17, 39, and 40). In contrast, pneumococcal toxins such as pneumolysin and hydrogen peroxide were reported to act as direct inducers of cell death and as immune activators in vitro and in vivo (41)(42)(43). Our observation that, in established meningitis (24 h postchallenge), the immune response did not differ between TLR2 Ϫ/Ϫ mice and wt littermates, hints at higher pneumococcal toxin concentrations as a major factor for deterioration to more severe CNS alterations and clinical symptoms in TLR2 Ϫ/Ϫ mice.…”

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

“…Increased mucus production can lead to airway obstruction which, in the setting of chronic inflammation, incapacitates the mucociliary escalator and impairs bacterial clearance. When bacterial load rises later in infection, increased bacterial autolysis releases lytic concentrations of pneumolysin, directly and significantly damaging the respiratory epithelium and facilitating dissemination of pneumococci from alveoli into the bloodstream (61)(62)(63).…”

Intermedilysin Is Essential for the Invasion of Hepatoma HepG2 Cells by Streptococcus intermedius

“…PLY (the closest CDC relative of ILY) was shown to facilitate pneumococcal invasion/ penetration and proliferation in alveolar cells and, following bacteremia (31), damage endothelial cells of the blood brain barrier (44) mouse (36). The cytolytic characteristics and steric molecular structure of ILY are similar to those of other CDCs (24,25,29), although ILY shows an unusual and perhaps significant species specificity for human cells and recognizes an alternative cell membrane receptor to cholesterol, the receptor molecule for typical CDCs (24,25).…”