Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fc1 heavy chain but not the antigen-binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease-resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate.
|Original language||English (US)|
|Number of pages||8|
|State||Published - Mar 2014|
Bibliographical noteFunding Information:
All human and mouse studies were approved by the Human and Animal Subjects Subcommittees, and written informed consent was obtained from patients. We thank Ann Emery for secretarial support. This work was supported by the National Institutes of Health Grants AI-092468, AI-48796, AI-42240, HD-41361, AI092468 (ENJ), AI-38446 (JNW), DE15844, the Tufts Digestive Disease Research Center P30 DK34928 (AGP), the Mucosal and Vaccine Research Center at the University of Colorado School of Medicine, and the Department of Veterans Affairs Research Service.