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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\n            <jats:named-content content-type=\"genus-species\">S. pneumoniae<\/jats:named-content>\n            , 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\n            <jats:italic>lytA ply<\/jats:italic>\n            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.\n          <\/jats:p>","DOI":"10.1128\/iai.02811-14","type":"journal-article","created":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T05:15:52Z","timestamp":1416287752000},"page":"591-603","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Pleiotropic Effects of Cell Wall Amidase LytA on Streptococcus pneumoniae Sensitivity to the Host Immune Response"],"prefix":"10.1128","volume":"83","author":[{"given":"Elisa","family":"Ramos-Sevillano","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas (CIB-CSIC), Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias 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