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O038 - COMPLEMENTARY MECHANISMS OF PROTECTION AGAINST STREPTOCOCCUS PNEUMONIAE BY IGA1 PROTEASE NEUTRALIZING ANTIBODY IN VITRO AND IN VIVO (ID 795)
Abstract
Background
Streptococcus pneumoniae, akin to multiple other invasive mucosal respiratory pathogens in humans, consistently produces a protease that cleaves the predominant antibody in the respiratory tract, IgA1. The protease is expressed on the bacterial surface, inhibits opsonophagocytosis (OPS) of the organism by IgA1 and facilitates its adherence to respiratory epithelial cells.
Methods
We expressed the full-length lytic protease and a nonfunctional single amino acid mutant and generated 4 murine monoclonal antibodies (mMAb IP01-4) that bound the protein and showed varying abilities to neutralize its proteolytic activity. Phagocytosis was performed with human and murine neutrophils and complement. Mice were infected intranasally.
Results
In vitro, neutralization proteolytic activity restored the ability of human capsule-specific IgA1 to effect complement-dependent OPS of S. pneumoniae. In vivo, mMab IP04 supported protection by human IgA1 of mice for survival after intranasal pneumococcal infection in vivo by both Fc- and F(ab’)2- dependent mechanisms. Neutralization by mMAb’s IP02 and IP04 was mediated by inhibition of binding of IgA1 to the protease, binding that was localized around key metalloproteinase site. Neutralizing mMAb IP04 inhibited cleavage of the Fc portion of IgA1 from the bacterial surface. In summary, antibodies generated to pneumococcal IgA1 protease prevent cleavage of this human antibody subclass, facilitate IgA1-dependent OPS in vitro and protect against fatal mucosal infection in vivo.
Conclusions
IgA1 protease may serve as an independent vaccine candidate or as an adjunct to polysaccharide or other pneumocccal protein vaccines to limit primary mucosal infections with this prominent human pathogen.