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oai:repisalud.isciii.es:20.500.12105/85922025-05-07T10:55:31Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16980

00925njm 22002777a 4500 dc Ramos-Sevillano, Elisa author Urzainqui, Ana author Campuzano, Susana author Moscoso, Miriam author Gonzalez-Camacho, Fernando author Domenech Lucas, Mirian author Rodriguez de Cordoba, Santiago author Sánchez Madrid, Francisco author Brown, Jeremy S author García, Ernesto author Yuste, Jose Enrique author 2015-02 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. Infect Immun. 2015 Feb;83(2):591-603. doi: 10.1128/IAI.02811-14. Epub 2014 Nov 17. 10.1128/IAI.02811-14 1098-5522 0019-9567 Infection and immunity 25404032 http://hdl.handle.net/20.500.12105/8592 Pleiotropic effects of cell wall amidase LytA on Streptococcus pneumoniae sensitivity to the host immune response