Cutting edge: a novel nonoxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth.
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.
del Cerro-Vadillo
Elida
E
Servicio de Inmunología, Hospital Universitario Marqués de Valdecilla, Servicio Cántabro de Salud, Santander, Spain.
Madrazo-Toca
Fidel
F
Carrasco-Marín
Eugenio
E
Fernandez-Prieto
Lorena
L
Beck
Christian
C
Leyva-Cobián
Francisco
F
Saftig
Paul
P
Alvarez-Dominguez
Carmen
C
D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000382:microbiology; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006460:Hemolysin Proteins; D007113:Immunity, Innate / Q000235:genetics; D007424:Intracellular Fluid / Q000378:metabolism / Q000382:microbiology; D008089:Listeria monocytogenes / Q000254:growth & development* / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology*; D037521:Virulence Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D037521:Virulence Factors; D002402:Cathepsin D; D020696:rab5 GTP-Binding Proteins; C038705:hlyA protein, Listeria monocytogenes