Pneumolysin-Induced Complement Depletion during Experimental Pneumococcal Bacteremia

Abstract

To quantify complement depletion by pneumolysin during Streptococcus pneumoniae bacteremia, cirrhotic and control rats were infected intravenously with one of three isogenic mutant strains of S. pneumoniae expressing different forms of pneumolysin. Outcome measures included clearance of the organisms from the bloodstream, alterations in 50% serum hemolytic complement (CH 50 ) activity and complement C3 levels during infection, and serum opsonic capacity at 18 h postinfection. Cirrhotic rats had significantly lower CH 50 and C3 levels than control rats, both before and after infection. However, initial complement levels did not predict bacterial load after 18 h of infection. Changes in CH 50 and C3 levels over the 18-h period correlated with numbers of H؉C؉ but not H؉C؊ or PLY؊ organisms in the bloodstream at 18 h postinfection. The sera of cirrhotic rats infected with the H؉C؉ strain had significantly decreased levels of C3 and showed significantly lower opsonizing activity for S. pneumoniae than sera from H؉C؉-infected control rats. These studies suggest that under limiting concentrations of complement, the expression of pneumolysin by pneumococci has a significant, negative effect on serum complement levels and reduces serum opsonic activity.

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

“…First, vaccination with PlyD1 leads to neutralization of Ply that in turn limits damage to the lung epithelium, which allows S. pneu- moniae entry into the vasculature and initiation of bacteremia and lethal sepsis, as stated above. Neutralizing Ply could also affect the level of virulence by limiting Ply-mediated complement depletion (38), prevention of phagocytosis by autolysis (39), and reduction in polymorphonuclear cell antibacterial properties (40). However, neutralizing Ply could reduce bacteremia (37), but the observed death in our PlyD1-vaccinated mice may indicate a reduction of bacteremia without a reduction in sepsis.…”

Replacing the 238th aspartic acid with an arginine impaired the oligomerization activity and inflammation-inducing property of pyolysin

“…PLY, one of the most extensively studied CDCs, exhibits several biological properties, such as activation of the complement system [20], platelets [21], and NLR family pyrin domain containing protein 3 (NLRP3) inflammasome [22] or stimulation of pattern recognition receptors (PRRs) [23,24]. Studies indicated that the pore-forming activity and pathogen-associated molecular pattern (PAMP) activity of the toxin form the foundation for most of the previously mentioned biological properties.…”

The Effects of PspC on Complement-Mediated Immunity to Streptococcus pneumoniae Vary with Strain Background and Capsular Serotype

“…The importance of complement for immunity to S. pneumoniae is emphasized by the identification of several mechanisms by which the bacteria can inhibit complement activity. The choline binding surface protein PspA and the capsule prevent C3b/iC3b deposition on S. pneumoniae by mechanisms that remain unclear, whereas the secreted toxin pneumolysin seems to divert classical pathway activity away from the bacteria (1,30,32,35,39,43,48).…”