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. 2007 Apr;75(4):1843-51.
doi: 10.1128/IAI.01384-06. Epub 2007 Jan 29.

Contributions of pneumolysin, pneumococcal surface protein A (PspA), and PspC to pathogenicity of Streptococcus pneumoniae D39 in a mouse model

Abiodun D Ogunniyi  1 , Kim S LeMessurier, Rikki M A Graham, James M Watt, David E Briles, Uwe H Stroeher, James C Paton
Affiliations

Contributions of pneumolysin, pneumococcal surface protein A (PspA), and PspC to pathogenicity of Streptococcus pneumoniae D39 in a mouse model

Abiodun D Ogunniyi et al. Infect Immun. 2007 Apr.

Abstract

Successful colonization of the upper respiratory tract by Streptococcus pneumoniae is an essential first step in the pathogenesis of pneumococcal disease. However, the bacterial and host factors that provoke the progression from asymptomatic colonization to invasive disease are yet to be fully defined. In this study, we investigated the effects of single and combined mutations in genes encoding pneumolysin (Ply), pneumococcal surface protein A (PspA), and pneumococcal surface protein C (PspC, also known as choline-binding protein A) on the pathogenicity of Streptococcus pneumoniae serotype 2 (D39) in mice. Following intranasal challenge with D39, stable colonization of the nasopharynx was maintained over a 7-day period at a level of approximately 10(5) bacteria per mouse. The abilities of the mutant deficient in PspA to colonize the nasopharynx and to cause lung infection and bacteremia were significantly reduced. Likewise, the PspC mutant and, to a lesser extent, the Ply mutant also had reduced abilities to colonize the nasopharynx. As expected, the double mutants colonized less well than the parent to various degrees and had difficulty translocating to the lungs and blood. A significant additive attenuation was observed for the double and triple mutants in pneumonia and systemic disease models. Surprisingly, the colonization profile of the derivative lacking all three proteins was similar to that of the wild type, indicating virulence gene compensation. These findings further demonstrate that the mechanism of pneumococcal pathogenesis is highly complex and multifactorial but ascribes a role for each of these virulence proteins, alone or in combination, in the process.

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Figures

FIG. 1.
FIG. 1.
Western immunoblot analysis of lysates of D39 and its isogenic derivatives deficient in PspA, PspC, and/or Ply after they were electroblotted onto nitrocellulose. The samples were reacted with polyclonal sera specific for the indicated antigens. Immunoreactive bands correspond to PspC (∼100 kDa) (row A), PspA (∼75 kDa) (row B), and Ply (∼50 kDa) (row C).
FIG. 2.
FIG. 2.
Bacterial recovery from the nasopharynx of CD1 mice after i.n. challenge with 2 × 107 to 3 × 107 CFU of D39 or its isogenic derivatives over a 7-day period. Pooled data from two independent experiments are shown. The horizontal broken lines indicate the median levels of colonization of each strain at each time point. Asterisks indicate points of statistical significance in comparison to the values for the D39 parent (*, P < 0.05; **, P < 0.01; ***, P < 0.001 [Mann-Whitney two-tailed tests]). The broken segment on the y axis (NC) indicates that no mouse was colonized at the indicated time points (limit of detection, 40 CFU).
FIG. 3.
FIG. 3.
Bacterial recovery from the lungs of CD1 mice after i.n. challenge with 2 × 107 to 3 × 107 CFU of D39 or its isogenic derivatives over a 7-day period. Pooled data from two independent experiments are shown. The horizontal broken lines indicate the median levels of lung invasion of each strain at each time point. Asterisks indicate points of statistical significance in comparison to the values for the D39 parent (*, P < 0.05; **, P < 0.01; ***, P < 0.001 [Mann-Whitney two-tailed tests]). The broken segment on the y axis (NI) indicates no lung infection at the indicated time points (limit of detection, 80 CFU). The lung CFU data are from the same mice for which data are shown in Fig. 2.
FIG. 4.
FIG. 4.
Survival times for mice after i.p. challenge. Groups of 10 BALB/c mice were challenged i.p. with approximately 1 × 106 CFU of the indicated strains. Each datum point represents one mouse. The horizontal broken lines denote the median survival times for each group.
FIG. 5.
FIG. 5.
Survival times for mice after i.n. challenge. Groups of 10 to 15 CBA/N (xid) mice were challenged i.n. with approximately 2 × 107 CFU of the indicated strains. Each datum point represents one mouse. The horizontal broken lines denote the median survival times for each group.
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