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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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 3

Cathepsin C and serine protease activities and cytokine/chemokine serum levels in Olfm4- and gp91phox-deficient mice.

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Cathepsin C and serine protease activities and cytokine/chemokine serum ...
(A–C) Neutrophils (5 × 106) derived from the bone marrow of mice with different genotypes 6 hours after i.p. infection with S. aureus (5 × 107 CFU per mouse) were lysed, and an equal amount of lysate was used for assays of cathepsin C (Cat C) (A), neutrophil elastase (B), and cathepsin G (Cat G) (C) activity using the corresponding AMC-labeled substrate. *P < 0.05 when compared with WT (gp91phox+/+Olfm4+/+) mice. Data are expressed as the mean ± SD (n = 5). RFU, relative fluorescence unit. (D) Cytokine and chemokine levels in the serum of mice with different genotypes 6 hours after i.p. infection with S. aureus (5 × 107 CFU per mouse) were determined by high-throughput immunoassay. Data are expressed as the mean ± SD for each experimental group (n = 5). *P < 0.05 versus WT (gp91phox+/+Olfm4+/+) mice.