TheStreptococcuspneumoniaeCapsule Inhibits Complement Activity and Neutrophil Phagocytosis by Multiple Mechanisms

Abstract

The Streptococcus pneumoniae capsule is vital for virulence and may inhibit complement activity and phagocytosis. However, there are only limited data on the mechanisms by which the capsule affects complement and the consequences for S. pneumoniae interactions with phagocytes. Using unencapsulated serotype 2 and 4 S. pneumoniae mutants, we have confirmed that the capsule has several effects on complement activity. The capsule impaired bacterial opsonization with C3b/iC3b by both the alternative and classical complement pathways and also inhibited conversion of C3b bound to the bacterial surface to iC3b. There was increased binding of the classical pathway mediators immunoglobulin G (IgG) and C-reactive protein (CRP) to unencapsulated S. pneumoniae, indicating that the capsule could inhibit classical pathway complement activity by masking antibody recognition of subcapsular antigens, as well as by inhibiting CRP binding. Cleavage of serum IgG by the enzyme IdeS reduced C3b/iC3b deposition on all of the strains, but there were still marked increases in C3b/iC3b deposition on unencapsulated TIGR4 and D39 strains compared to encapsulated strains, suggesting that the capsule inhibits both IgG-mediated and IgG-independent complement activity against S. pneumoniae. Unencapsulated strains were more susceptible to neutrophil phagocytosis after incubation in normal serum, normal serum treated with IdeS, complement-deficient serum, and complement-deficient serum treated with IdeS or in buffer alone, suggesting that the capsule inhibits phagocytosis mediated by Fc␥ receptors, complement receptors, and nonopsonic receptors. Overall, these data show that the S. pneumoniae capsule affects multiple aspects of complement-and neutrophil-mediated immunity, resulting in a profound inhibition of opsonophagocytosis.The Gram-positive pathogen Streptococcus pneumoniae is one of the most common causes of pneumonia, septicemia, and meningitis in children and adults in both industrialized and developing parts of the world (10). This large burden of disease is compounded by the increased incidence of S. pneumoniae infections associated with HIV and by increasing antibiotic resistance among clinical isolates, and there is a strong need to understand the molecular pathogenesis of S. pneumoniae infections to assist the development of new therapeutic targets. Probably the most important virulence factor for S. pneumoniae is the extracellular capsule, a layer consisting of chains of monosaccharides that surrounds the bacteria. For S. pneumoniae strains, there are 91 antigenically distinct capsular serotypes, dictated by the order and type of the monosaccharide units within the polysaccharide chain and by different side branches (5, 27). The importance of the S. pneumoniae capsule for virulence is demonstrated by the facts that (i) all clinical isolates causing invasive disease are encapsulated; (ii) loss of the capsule by either genetic mutation or enzymatic degradation dramatically reduces S. pneumoniae virulence in animal models of infection ...

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