Given that Streptococcus pneumoniae can cause life-threatening pulmonary and systemic infection, an apparent paradox is that the bacterium resides, usually harmlessly, in the nasopharynx of many people. Humoral immunity is thought to be the primary defense against serious pneumococcal infection, and we hypothesized that nasopharyngeal colonization of mice results in the generation of an antibody response that provides long-term protection against lung infection. We found that survival of of C57L/6 mice after intranasal inoculation with wild-type serotype 4 strain TIGR4 pneumococci required B cells but not T cells, suggesting that nasopharyngeal colonization elicited a protective humoral immune response. In fact, intranasal inoculation resulted in detectable pneumococcal-specific antibody responses, and protected mice against a subsequent high-dose S. pneumoniae pulmonary challenge. B cells were required for this response, and transfer of immune sera from i.n. colonized mice, or monoclonal antibodies against phosphorylcholine, a common surface antigen of S. pneumoniae, was sufficient to confer protection. IgA, which is thought to participate in mucosal immunity, contributed to but was not absolutely required for protection from pulmonary challenge. Protection induced by i.n. colonization lasted at least ten weeks. Although it was partially dependent on T cells, depletion of CD4+ T cells at the time of challenge did not alter protection, suggesting that T cells did not provide essential help in activation of conventional memory cells. Peritoneal B1b cells and radiation-resistant, long-lived antibody secreting cells have previously been shown to secrete anti-pneumococcal antibodies and mediate protection against systemic infection following immunization with killed bacteria or capsular polysaccharide [1, 2]. We found that peritoneal cells were not sufficient for colonization-induced protection, but sub-lethally irradiated mice largely survived pulmonary challenge. Thus, our results are consistent with the hypothesis that nasopharyngeal colonization, a common occurrence in humans, is capable of eliciting extended protection against invasive pneumococcal disease by generating long-lived antibody-secreting cells.

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