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Published on: February 10, 2011
Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease
Wenli Liu1, Ming Yan, Janyce A Sugui
1Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
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.
Insights
Deleting Olfactomedin 4 (OLFM4) enhances immune defense against Staphylococcus aureus infections in a mouse model of chronic granulomatous disease (CGD). However, it did not improve defense against Aspergillus fumigatus.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Chronic granulomatous disease (CGD) is characterized by recurrent, life-threatening bacterial and fungal infections.
- Olfactomedin 4 (OLFM4), a neutrophil granule protein, is known to negatively regulate host defense against bacterial infections.
Purpose of the Study:
- To investigate the effect of Olfm4 deletion on host defense against Staphylococcus aureus and Aspergillus fumigatus in a murine X-linked gp91phox-deficiency CGD model.
Main Methods:
- Utilized a murine X-linked gp91phox-deficiency CGD model.
- Assessed host defense mechanisms, including intracellular killing, in vivo clearance, and sepsis resistance against S. aureus.
- Evaluated immune responses by measuring protease activities and serum cytokine levels.
- Used a lung infection model to test defense against Aspergillus fumigatus.
Main Results:
- Mice deficient in both gp91phox and Olfm4 showed significantly enhanced intracellular killing and in vivo clearance of S. aureus compared to CGD mice.
- Resistance to S. aureus sepsis was also significantly increased in double-deficient mice.
- Activities of cathepsin C and downstream proteases, along with serum levels of various cytokines and chemokines, were elevated in Olfm4-deficient mice after S. aureus challenge.
- No enhanced defense against A. fumigatus was observed in Olfm4-deficient mice.
Conclusions:
- Olfactomedin 4 (OLFM4) deletion enhances immune defense against Staphylococcus aureus in a CGD mouse model.
- OLFM4 deletion does not improve defense against Aspergillus fumigatus in this model.
- OLFM4 represents a potential therapeutic target for augmenting bacterial infection defense in CGD patients.
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