A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

• Published in: PLoS pathogens 2011-01, Vol.7 (1), p.e1001262-e1001262
• Main Authors: Bewley, Martin A, Marriott, Helen M, Tulone, Calogero, Francis, Sheila E, Mitchell, Timothy J, Read, Robert C, Chain, Benny, Kroemer, Guido, Whyte, Moira K B, Dockrell, David H
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bacteria; Bacterial pneumonia; Bone marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cathepsin D - deficiency; Cathepsin D - genetics; Cathepsin D - metabolism; Cathepsins; Cell Biology/Cellular Death and Stress Responses; Cell Line, Tumor; Cytosol - enzymology; Cytosol - microbiology; Development and progression; Female; Genetic aspects; Homeostasis; Host-Pathogen Interactions; Humans; Immunology/Immune Response; Infectious Diseases/Bacterial Infections; Intracellular Membranes - enzymology; Intracellular Membranes - microbiology; Macrophages; Macrophages - enzymology; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Phagosomes - enzymology; Phagosomes - microbiology; Physiological aspects; Pneumonia; Respiratory Medicine/Respiratory Infections; Rodents; Streptococcus infections; Streptococcus pneumoniae; Streptococcus pneumoniae - pathogenicity; Streptococcus pneumoniae - physiology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001262

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D(-/-) hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function.