Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease
Wenli Liu, … , William G. Coleman, Griffin P. Rodgers
Wenli Liu, … , William G. Coleman, Griffin P. Rodgers
Published August 1, 2013
Citation Information: J Clin Invest. 2013;123(9):3751-3755. https://doi.org/10.1172/JCI68453.
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Brief Report Immunology

Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease

Abstract

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.

Authors

Wenli Liu, Ming Yan, Janyce A. Sugui, Hongzhen Li, Chengfu Xu, Jungsoo Joo, Kyung J. Kwon-Chung, William G. Coleman, Griffin P. Rodgers

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Figure 1

Intracellular killing and in vivo peritoneal clearance of S. aureus in Olfm4- and gp91phox-deficient mice.

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Intracellular killing and in vivo peritoneal clearance of S. aureus in O...
(A) NBT assays and (B) superoxide burst assays were performed to confirm the loss of NAPDH oxidase activity in different genotypes of mice. Original magnification, ×200 in NBT assays. (C) Neutrophils derived from the bone marrow of Olfm4- and gp91phox-deficient mice were incubated with preopsonized S. aureus (Rosenbach or USA300). The number of viable bacteria (CFU) after the cells were treated with gentamicin (50 μg/ml) was determined on plates. Data are expressed as the mean ± SD (n = 5). (D) Mice were challenged i.p. with S. aureus (Rosenbach or USA300). After 6 hours, the peritoneal cavity was lavaged, and the number of viable bacteria (CFU) was determined on plates. Data are expressed as the mean ± SD (n = 5). *P < 0.05 when compared with WT (gp91phox+/+Olfm4+/+) mice or as indicated.