Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease

• Published in: The Journal of clinical investigation Vol. 123; no. 9; pp. 3751 - 3755
• Main Authors: Liu, Wenli, Yan, Ming, Sugui, Janyce A, Li, Hongzhen, Xu, Chengfu, Joo, Jungsoo, Kwon-Chung, Kyung J, Coleman, William G, Rodgers, Griffin P
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2013
• Subjects: Animals; Aspergillosis - blood; Aspergillosis - immunology; Aspergillosis - microbiology; Aspergillus fumigatus; Aspergillus fumigatus - immunology; Bacteria; Bacterial infections; Biomedical research; Bone marrow; Brief Report; Cathepsin C - metabolism; Chronic granulomatous disease; Cytokines - blood; Disease; Gene Deletion; Glycoproteins - genetics; Glycoproteins - metabolism; Granulomatous Disease, Chronic - blood; Granulomatous Disease, Chronic - complications; Granulomatous Disease, Chronic - enzymology; Immunity; Male; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Mortality; NADPH Oxidase 2; NADPH Oxidases - deficiency; NADPH Oxidases - genetics; Neutrophils - enzymology; Patients; Rodents; Staphylococcal Infections - blood; Staphylococcal Infections - immunology; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - immunology; Staphylococcus infections; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI68453

Chronic granulomatous disease (CGD) patients have recurrent life-threatening bacterial and fungal infections. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that negatively regulates host defense against bacterial infection. The goal of this study was to evaluate the impact of Olfm4 deletion on host defense against Staphylococcus aureus and Aspergillus fumigatus in a murine X-linked gp91phox-deficiency CGD model. We found that intracellular killing and in vivo clearance of S. aureus, as well as resistance to S. aureus sepsis, were significantly increased in gp91phox and Olfm4 double-deficient mice compared with CGD mice. The activities of cathepsin C and its downstream proteases (neutrophil elastase and cathepsin G) and serum levels of IL-1β, IL-6, IL-12p40, CXCL2, G-CSF, and GM-CSF in Olfm4-deficient as well as gp91phox and Olfm4 double-deficient mice were significantly higher than those in WT and CGD mice after challenge with S. aureus. We did not observe enhanced defense against A. fumigatus in Olfm4-deficient mice using a lung infection model. These results show that Olfm4 deletion can successfully enhance immune defense against S. aureus, but not A. fumigatus, in CGD mice. These data suggest that OLFM4 may be an important target in CGD patients for the augmentation of host defense against bacterial infection.