Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8592
Pleiotropic effects of cell wall amidase LytA on Streptococcus pneumoniae sensitivity to the host immune response
Ramos-Sevillano, Elisa ISCIII | Urzainqui, Ana | Campuzano, Susana | Moscoso, Miriam | Gonzalez-Camacho, Fernando ISCIII | Domenech Lucas, Mirian ISCIII | Rodríguez de Córdoba, Santiago | Sanchez-Madrid, Francisco CNIC | Brown, Jeremy S | García, Ernesto | Yuste, Jose Enrique ISCIII
Infect Immun. 2015 Feb;83(2):591-603. doi: 10.1128/IAI.02811-14. Epub 2014 Nov 17.
The complement system is a key component of the host immune response for the recognition and clearance of Streptococcus pneumoniae. In this study, we demonstrate that the amidase LytA, the main pneumococcal autolysin, inhibits complement-mediated immunity independently of effects on pneumolysin by a complex process of impaired complement activation, increased binding of complement regulators, and direct degradation of complement C3. The use of human sera depleted of either C1q or factor B confirmed that LytA prevented activation of both the classical and alternative pathways, whereas pneumolysin inhibited only the classical pathway. LytA prevented binding of C1q and the acute-phase protein C-reactive protein to S. pneumoniae, thereby reducing activation of the classical pathway on the bacterial surface. In addition, LytA increased recruitment of the complement downregulators C4BP and factor H to the pneumococcal cell wall and directly cleaved C3b and iC3b to generate degradation products. As a consequence, C3b deposition and phagocytosis increased in the absence of LytA and were markedly enhanced for the lytA ply double mutant, confirming that a combination of LytA and Ply is essential for the establishment of pneumococcal pneumonia and sepsis in a murine model of infection. These data demonstrate that LytA has pleiotropic effects on complement activation, a finding which, in combination with the effects of pneumolysin on complement to assist with pneumococcal complement evasion, confirms a major role of both proteins for the full virulence of the microorganism during septicemia.
Animals | Bacterial Capsules | Bacterial Proteins | Cell Wall | Complement Activation | Complement C3 | Complement Factor H | Histocompatibility Antigens | Host-Pathogen Interactions | Mice | Mice, Inbred C57BL | N-Acetylmuramoyl-L-alanine Amidase | Phagocytosis | Phosphorylcholine | Pneumococcal Infections | Polysaccharides, Bacterial | Sepsis | Streptococcus pneumoniae | Streptolysins
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