Antibody mediated immunity against serotype 8 Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae (pneumococcus) is the common cause of otitis media, community acquired pneumonia and meningitis. Pneumococcal capsular polysaccharide (PS) vaccines were designed to prevent pneumococcal disease. Studies show that IgM, IgG and IgA are generated in response to PS vaccination, but opsonic IgG is thought to confer immunity. The role of IgM and IgA in protection against pneumococcal disease is not well understood. To investigate the efficacy of these isotypes against pneumococcal infection, I studied the ability of serotype-specific human monoclonal antibodies (MAbs) to protect mice from death in systemic and pulmonary infection models.;MAb D11, a human IgM specific for PS from pneumococcal serotype 8 (PS 8), was isolated after EBV transformation of peripheral B lymphocytes from a Pneumovax vaccine recipient. In vitro, D11 mediated complement deposition onto the surface of the pneumococcus via the classical and alternative complement pathways. In vivo, D11 protected wild type and classical complement pathway knock-out (C4 KO) mice against systemic lethal serotype 8 infection. Reconstitution experiments showed that D11 protected C3 knock-out (C3 KO) mice when the alternative complement pathway was intact. An intratracheal model of pneumococcal pneumonia was developed to study the in vivo efficacy of D11 and NAD, a PS 8-specific human IgA. Both MAbs protected C4 KO mice from death from pneumococcal pneumonia. In vitro studies to understand the mechanism of D11- and NAD-mediated protection revealed that neither MAb promoted opsonophagocytic killing via human PMNs. However, D11 and NAD mediated a decrease in IL-8 secretion from human PMNs in vitro.;To further understand the role of MAb on the inflammatory response, the intratracheal infection model was used to study the effect of D11 on the pathogenesis of pneumococcal infection. In this model, D11-mediated protection was associated with absence of bacteremia, and reduction in lung bacterial burden, in serum and lung proinflammatory cytokine and chemokine, and in lung cytokine and chemokine mRNA expression, 24 hours post-infection, all compared to control mice given an irrelevant IgM or PBS.;The data suggest a novel mechanism of antibody mediated immunity to pneumococcus, which is to modulate the inflammatory response to limit host damage.