Pneumococcal IgA1 protease subverts specific protection by human IgA1

Abstract

Bacterial 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 (hMAb's), 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 hMAb's 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.

Polysaccharide-Specific Memory B Cells Predict Protection against Experimental Human Pneumococcal Carriage

“…IgA1 accounts for approximately 90% of all IgA found in peripheral blood and the upper respiratory tract (23,24). S. pneumoniae is able to cleave IgA1, via IgA1 protease, a mechanism that facilitates pneumococcal adherence to the epithelium and abrogates the protective effects of IgA (25). As a result, we hypothesize that protection against colonization was associated with PS IgG-secreting B MEM populations rather than PS IgA-secreting B MEM populations because of the advantage conferred through the generation of IgG-rather than IgA-based responses.…”

Interleukin‐10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae

“…5 S. pneumoniae contains several virulence factors used to evade the immune response at different stages of infection. [6][7][8] For instance, this bacterium is able to prevent phagocytosis and complement binding, induce necrosis of immune cells and cleavage of IgA antibodies.…”

Respiratory Bacterial Vaccines

“…In this interval, expression of one of two IgA1 proteases (igaB) (Poole et al, 2013) also increased. IgA1 proteases cleave the phagocytebinding effector Fc fragment from the bacterial-bound Fab fragments of IgA1, the predominant antibody in the upper respiratory mucosa, thereby inhibiting bacterial lysis (H. influenzae) or phagocytosis (S. pneumoniae) (Fasching et al, 2007;Janoff et al, 2013). As has been shown with S. pneumoniae, such cleavage of Fcα may also enhance adherence of encapsulated strains (Weiser et al, 2003).…”

“…In addition, pneumococcal neuraminidase may enhance bacterial attachment by exposing cellular binding sites. Finally, pneumococcal IgA1 protease, which cleaves the effector Fc portion of IgA1 from its pathogen-binding component, may facilitate epithelial cell binding, inhibit agglutination, and disrupt functional bacterial opsonization and killing by polymeric and mucosal IgA1 (Fasching et al, 2007;Janoff et al, 2013;Kilian et al, 1988;Weiser et al, 2003). In addition to phosphorylcholine, putative surface adhesins include PsaA that facilitates in vivo colonization and bacterial adherence in vitro (Paton et al, 1993;Tuomanen et al, 1995).…”