Deletion of OLFM4 rescues defective host defense against Staphylococcus aureus, but not Aspergillus fumigatus in murine X-linked chronic granulomatous disease (P1259)

Abstract

Abstract Chronic granulomatous disease (CGD) patients have recurrent life-threating bacterial and fungal infections due to the mutation of one of four subunits of the respiratory burst oxidase (NADPH-oxidase). Olfactomedin 4 (OLFM4) is a neutrophil granule protein, which has been recently identified as a negative regulator of host innate immunity against bacteria infection in mice through modulation of neutrophil protease activity. The goal of this study was to evaluate the impact of OLFM4 deletion on host innate immunity against Staphylococcus aureus and Aspergillus fumigatus, in a murine X-linked CGD model. We found that neutrophil intracellular killing and in vivo clearance of S. aureus have been significantly increased in gp91phox- and OLFM4-double deficiency mice compared with CGD mice. The mice survival to S. aureus sepsis in gp91phox- and OLFM4-double deficiency mice has also been significantly prolonged compared with CGD mice. Cathepsin C activities in OLFM4 deficient as well as double deficient mice neutrophils were significantly higher than those in WT mouse neutrophils. Accordingly, the elastase and cathepsin G activities in the neutrophils of OLFM4 deficient and double deficient mice were also substantially higher than those in WT mice as well as CGD mice. However, we have not observed enhanced innate immunity against A. fumigatus in OLFM4 deficiency mice. OLFM4 might prove to be an important target in CGD patients to augment host defense against bacterial infection.