Pneumococcal IgA1 protease subverts specific protection by human IgA1
Edward N. JanoffJeffrey B. RubinsC E FaschingDarlene CharboneauJeremy RahkolaAndrew G. PlautJeffrey N. Weiser
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Abstract:
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 Fcα1 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.Keywords:
Immunoglobulin A
Pneumococcal infections
Abstract Streptococcus pneumoniae (S. pneumoniae) is a significant Gram-positive opportunistic pathogen responsible for a variety of lethal infections. This bacterium accounts for more deaths from diseases than any other single pathogen worldwide. Distinctively, these symptoms arise despite effective antibiotic therapy. This study unveiled a novel mechanism of resistance to S. pneumoniae infection by targeting pneumolysin (PLY) and sortase A (Srt A), the key virulence factors of S. pneumoniae. Through protein phenotype assays, we found alnustone to be a potent drug that inhibits both PLY and Srt A. Using a PLY-mediated hemolysis assay, we found that albumin can effectively reduce Srt A peptidase activity by blocking PLY oligomerization, thereby directly inhibiting PLY-expressing cytolysis. Co-incubation of S. pneumoniae D39 Srt A with small-molecule inhibitors reduces cell wall-bound Nan A (pneumococcal-anchored surface protein Srt A), inhibits biofilm formation, and significantly reduces biomass. But more interestingly, the protective effect of invasive pneumococcal disease (IPD) on murine streptococcus pneumoniae was further demonstrated. Our study proposes a detailed bacteriostatic mechanism of pneumococcal and highlights the major translational potential of targeting circulating PLY and Srt A to protect against pneumococcal infections. Our results suggest that the antiviral strategy of directly targeting PLY and Srt A with alnustone is a promising treatment option for Streptococcus pneumoniae and that alnustone can be used as an effective inhibitor of PLY and Srt A.
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C-reactive protein (CRP) has several properties that suggest that it may function as a bacterial opsonin. CRP shows binding reactivity with pneumococcal C-polysaccharide, the cell wall carbohydrate of Streptococcus pneumoniae. In this study we have demonstrated protection of mice against serotypes 3 and 4 of S. pneumoniae infection by a single prior injection of CRP. This effect was seen both in mice that lacked antibody to phosphocholine and in normal mice. Thus the opsonic properties of CRP previously described may be related to protection against pneumococcal infection.
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Streptococcus pneumoniae continues to be an important bacterial pathogen associated with invasive (e.g. bacteraemia) and non-invasive (e.g. community-acquired respiratory tract) infections worldwide. Surveillance studies conducted nationally and globally can assist in determining trends across geographical areas and allow comparisons between countries. SAVE is an ongoing, annual, national study focused on characterizing invasive isolates of S. pneumoniae obtained across Canada. This Supplement documents the initial 5 years of the SAVE study (2011-15) during which 6207 invasive isolates of S. pneumoniae were evaluated. The three manuscripts in this Supplement provide a comprehensive examination of the changing patterns of invasive S. pneumoniae obtained across Canada over a 5 year period. The data highlight the evolution of S. pneumoniae antimicrobial resistance and multidrug resistance, serotype distribution, genotypic relatedness and virulence under pressure by vaccination and antimicrobial usage. This allows both clinicians and researchers nationally and globally to view the current status of invasive pneumococcal infections in Canada.
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Streptococcus pneumoniae cell wall and cytoplasmic proteins contribute directly to pathogenesis of pneumococcal infection. Protective effect of pneumococcal proteins such as pneumolysin (Ply), muramylamidase (LytA) and pneumococcal surface protein A (PspA). There is discussion in the literature about development of conjugared pneumococcal vaccines, which should include polysaccharides of invasive serotypes of pneumococci as well as protein antigens of this pathogen, for prevention of infections caused by S. pneumoniae. Researches suggest that such hybrid vaccines will be effective, first of all, for children 65 years old because immune response to polysaccharide vaccines either do not form at all or insufficient for prevention of pneumococcal infection.
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Pneumococcal infections
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Streptococcus pneumoniae has demonstrated a remarkable ability to adapt during the conjugate vaccine era. The increasing incidence of serotype 35B disease and emergence of a multidrug-resistant clone reported in this issue of the Journal of Clinical Microbiology (L. Olarte et al., J Clin Microbiol 55:724-734, 2017, https://doi.org/10.1128/JCM.01778-16) underscore the limitations of pneumococcal vaccines that target the polysaccharide capsule.
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Pneumococcal Conjugate Vaccine
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Capsular types of pneumococci from normally sterile body sites of 1,622 patients in Brazil were analyzed. Of 1,477 isolates from cerebrospinal fluid, 76.1% were of types represented in the currently available pneumococcal vaccine. The importance of age, time, and place in determining the optimal formulation of pneumococcal vaccine is considered.
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