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. 2005 Nov;73(11):7718-26.
doi: 10.1128/IAI.73.11.7718-7726.2005.

Host and bacterial factors contributing to the clearance of colonization by Streptococcus pneumoniae in a murine model

Annemarie M C van Rossum  1 , Elena S Lysenko, Jeffrey N Weiser
Affiliations

Host and bacterial factors contributing to the clearance of colonization by Streptococcus pneumoniae in a murine model

Annemarie M C van Rossum et al. Infect Immun. 2005 Nov.

Abstract

Nasopharyngeal colonization is the first step in the interaction between Streptococcus pneumoniae (the pneumococcus) and its human host. Factors that contribute to clearance of colonization are likely to affect the spread of the pneumococcus and the rate of pneumococcal disease in the population. To identify host and bacterial factors contributing to this process, we examined the time course of colonization using genetically modified mice and pneumococci. Severe combined immunodeficient mice remained persistently colonized (>6 weeks). Major histocompatibility complex II-deficient mice, but not microMT mice, were unable to clear colonization and showed a diminished T helper 1 response. Thus, CD4+ T cells, rather than the generation of specific antibody, appear to be required for effective Th1-mediated clearance. In addition, the microbial pattern recognition receptor toll-like receptor 2 (TLR2), but not TLR4, was necessary for efficient clearance of colonization. In contrast, no role of complement component 3, inducible nitric oxide synthetase, interleukin 12 (IL-12), or IL-4 could be demonstrated. Expression of the pneumococcal toxin pneumolysin enhanced acute localized inflammatory responses and promoted clearance of colonization in a TLR4-independent manner. We conclude that both innate and CD4+ T-cell-mediated immunity and proinflammatory bacterial factors, rather than a humoral adaptive immune response, are important for clearance of S. pneumoniae from the murine nasopharynx.

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Figures

FIG. 1.
FIG. 1.
Comparison of the density of colonization in C57BL/6 (filled diamonds) versus C57BL/6 TLR2−/− (open squares) mice (A) or in C3H/HeOuJ (TLR4-sufficient) parental (filled diamonds) versus C3H/HeJ (TLR4-deficient) (open squares) mice (B) over time. The density of pneumococci in upper respiratory tract lavage specimens is expressed as the mean log CFU/ml ± the standard error of the mean. n = 5 to 15 mice per group per time point. *, P < 0.05.
FIG. 2.
FIG. 2.
Comparison of the density of colonization in C57BL/6 parental (filled diamonds), C57BL/6 SCID (open triangles), and C57BL/6 MHC-II−/− (open squares) mice over time. Values shown are mean log CFU/ml ± standard errors of the means. Five to 15 (C57BL/6), 5 to 10 (C57BL/6 SCID), and 9 (C57BL/6 MHC-II−/−) mice were used per group per time point. *, P < 0.05 for C57BL/6 wild-type mice compared to C57BL/6 MHC-II−/− mice; **, P < 0.05 C57BL/6 wild-type mice compared to C57BL/6 SCID mice.
FIG. 3.
FIG. 3.
Comparison of the distribution of serum IgG isotypes against a fragment of pneumococcal surface protein A (PspA) of strain P1121 in C57BL/6 (filled squares) and MHC-II−/− (open squares) mice colonized for 42 and 56 days, respectively. Values shown are mean titers ± standard errors of the means. n = 5 to 15 mice per group per time point. *, P < 0.05 for C57BL/6 wild-type mice compared to C57BL/6 MHC-II−/− mice.
FIG. 4.
FIG. 4.
Comparison of the density of colonization in C57BL/6 (A) or C3H (B) mice inoculated with P1121 (closed diamonds) or the P1121 ply-negative mutant (open squares) over time. Values shown are mean log CFU/ml ± standard errors of the means. n = 10 to 15 mice per group per time point. *, P < 0.05 for comparison between P1121 and the P1121 ply-negative mutant.
FIG. 5.
FIG. 5.
(A) MIP-2 levels in upper respiratory tract lavage specimens from C57BL/6 mice inoculated with P1121 (gray bar) or the P1121 ply-negative mutant (white bar). Values shown are mean concentrations (pg/ml) equalized for total protein content (μg/ml) ± standard errors of the means. n = 10 to 15 mice per group per time point. *, P < 0.05 for comparison between P1121 and the P1121 ply-negative mutant. (B) H&E-stained parasagittal sections of the anterior paranasal tissues of C3H/HeOuJ (TLR4-sufficient) mice 24 h after inoculation with P1121 (panel 1) or the P1121 ply-negative mutant (panel 2). Arrow indicates a neutrophilic infiltrate in the lumen of the paranasal spaces between the mucosal surfaces of turbinates in the P1121-colonized mouse. Magnification, ×200.
FIG. 5.
FIG. 5.
(A) MIP-2 levels in upper respiratory tract lavage specimens from C57BL/6 mice inoculated with P1121 (gray bar) or the P1121 ply-negative mutant (white bar). Values shown are mean concentrations (pg/ml) equalized for total protein content (μg/ml) ± standard errors of the means. n = 10 to 15 mice per group per time point. *, P < 0.05 for comparison between P1121 and the P1121 ply-negative mutant. (B) H&E-stained parasagittal sections of the anterior paranasal tissues of C3H/HeOuJ (TLR4-sufficient) mice 24 h after inoculation with P1121 (panel 1) or the P1121 ply-negative mutant (panel 2). Arrow indicates a neutrophilic infiltrate in the lumen of the paranasal spaces between the mucosal surfaces of turbinates in the P1121-colonized mouse. Magnification, ×200.
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