Streptococcus pneumoniae Surface Protein PcpA Elicits Protection against Lung Infection and Fatal Sepsis

Abstract

Previous studies have suggested that pneumococcal choline binding protein A (PcpA) is important for the full virulence of Streptococcus pneumoniae, and its amino acid sequence suggests that it may play a role in cellular adherence. PcpA is under the control of a manganese-dependent regulator and is only expressed at low manganese concentrations, similar to those found in the blood and lungs. PcpA expression is repressed under high manganese concentrations, similar to those found in secretions. In this study, we have demonstrated that PcpA elicits statistically significant protection in murine models of pneumonia and sepsis. In the model of pneumonia with each of four challenge strains, statistically fewer S. pneumoniae cells were recovered from the lungs of mice immunized with PcpA and alum versus mice immunized with alum only. The immunizations reduced the median CFU by 4-to 400-fold (average of 28-fold). In the model of sepsis using strain TIGR4, PcpA expression resulted in shorter times to become moribund and subcutaneous immunization with PcpA increased survival times of mice infected with wild-type PcpA-expressing pneumococci.

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

“…PcpA is under the control of a manganese (Mn)-dependent regulator, PsaR, and the Mn concentration in the NP of mice has been shown to result in downregulation of pcpA expression (19). The antibody response elicited by recombinant PcpA vaccination has been shown to provide protection against systemic infection (18) but not against colonization (21) in mice. However, we have shown that commensal NP colonization of children results in production of mucosal and serum antibodies (16,22,23), strongly suggesting that expression of PcpA occurs in the NP of children, unlike mice.…”

“…The pcpA gene has been shown to be conserved among 25 different strains examined (18), and PcpA protein is surface exposed (18). PcpA is not required for NP colonization of the mouse (18,19) but is indispensable for murine lung infection (20). PcpA is under the control of a manganese (Mn)-dependent regulator, PsaR, and the Mn concentration in the NP of mice has been shown to result in downregulation of pcpA expression (19).…”

“…Pneumococcal choline-binding protein A (PcpA) is distinct from other S. pneumoniae choline-binding proteins (CbpA and PspC) (17). The pcpA gene has been shown to be conserved among 25 different strains examined (18), and PcpA protein is surface exposed (18). PcpA is not required for NP colonization of the mouse (18,19) but is indispensable for murine lung infection (20).…”

Evaluation of a Vaccine Formulation against Streptococcus pneumoniae Based on Choline-Binding Proteins

“…The genome of the R6 strain does not have CbpI and CbpJ (8). Some of the CBPs, including PspA, PspC, and PcpA, have been described to be important virulence factors (7,(11)(12)(13), and PspA has been shown to be the major protein among the CBPs (14,15).…”

“…Both procedures have the advantage that they would be expected to also elute some of the other CBPs, many of which have been shown to be virulence factors for pneumococci that are capable of eliciting measurable protection against colonization and/or invasive disease in mice (12,29). The purpose of these studies is to confirm some of the earlier work and to do the studies on a somewhat larger scale to determine whether it is possible and desirable to attempt to use one of these approaches to produce a pneumococcal vaccine.…”