Monoclonal Antibody Requires Fc Receptor III and Macrophages To Mediate Protection against Pneumococcal Pneumonia in Mice

Antibodies to pneumococcal capsular polysaccharide (PPS) are required for PPS-based vaccine-mediated protection against Streptococcus pneumoniae. Previous work established that 1E2, a mouse IgG1 to PPS3 that does not induce serotype 3 (ST3) S. pneumoniae killing by phagocytes in vitro, protects mice from death after intranasal infection with ST3, but its efficacy was ab-rogated in FcR (F common gamma receptor)-deficient mice. In this study, we determined whether 1E2 efficacy against pulmo-nary ST3 infection requires FcRIII. 1E2 did not protect FcRIII-deficient (FcRIII/) mice. Studies of the mechanism of 1E2-mediated effects showed that it resulted in a marked reduction in lung inflammation in ST3-infected wild-type (Wt [C57BL/6]) mice that was abrogated in FcRIII/mice. 1E2 had no effect on early bacterial clearance in the lungs of ST3-infectedWt, FcRIIB/, or FcRIII/mice, but it reduced levels of bacteremia and serummacrophage inflammatory protein-2) (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-) inWt and FcRIIB/mice, strains in which it is protective. As previous work showed that neutrophils were dispensable for 1E2 efficacy, we investigated whether macrophages are required for 1E2 efficacy against intranasal infection with ST3 and found that its efficacy was abrogated inWtmice depleted of macrophages intranasally. In vitro studies revealed that1E2 promoted ST3 internalization by naïve alveolar macrophages but did not induce early intracellular killing. Macrophages from 1E2-treated ST3-infected mice studied ex vivo exhibited more apoptosis than those from FcRIII/mice. These findings suggest that 1E2mediates protection against ST3 in mice by affecting the inflammatory response, perhaps in part via macrophage apoptosis, rather than by inducing early bacterial clearance