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Cutting Edge: A Novel Nonoxidative Phagosomal Mechanism Exerted by Cathepsin-D Controls Listeria monocytogenes Intracellular Growth¹

Elida del Cerro-Vadillo^2,*, Fidel Madrazo-Toca^2,*, Eugenio Carrasco-Marín^*, Lorena Fernandez-Prieto^*, Christian Beck, Francisco Leyva-Cobián^*, Paul Saftig^2, and Carmen Alvarez-Dominguez^2,3,*

^* Servicio de Inmunología, Hospital Universitario Marqués de Valdecilla, Servicio Cántabro de Salud, Santander, Spain; and Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany

Deciphering how Listeria monocytogenes exploits the host cell machinery to invade mammalian cells is a key issue in understanding the pathogenesis of this food-borne pathogen, which can cause diseases ranging from gastroenteritis to meningitis and abortion. In this study, we show that the lysosomal aspartyl-protease cathepsin-D (Ctsd) is of considerable importance for nonoxidative listericidal defense mechanisms. We observed enhanced susceptibility to L. monocytogenes infection of fibroblasts and bone-marrow macrophages and increased intraphagosomal viability of bacteria in fibroblasts isolated from Ctsd-deficient mice compared with wild type. These findings are further supported by prolonged survival of L. monocytogenes in Ctsd-deficient mice after infection. Transient transfection of Ctsd in wild-type cells was sufficient to revert these wild-type phagosomes back to microbicidal compartments. Based on infection experiments with mutant bacteria, in vitro degradation, and immunoprecipitation experiments, we suggest that a major target of cathepsin D is the main virulence factor listeriolysin O.