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Improving White Blood Cell Defense Against Bacteria

A recent study has shown that deletion of a protein in white blood cells improves their ability to eradicate infections with the bacteria Staphylococcus aureus (S. aureus), although not the fungus Aspergillus fumigatus (A. fumigatus), in an animal model of chronic granulomatous disease (CGD).

CGD is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Individuals with CGD have recurrent bacterial and fungal infections, and often have areas of inflammation (granulomas) in various tissues that can cause damage. The body’s white blood cells normally eliminate bacteria via two modes of action—a non-oxidative mode of action that involves the use of specialized enzymes to attack and cleave proteins that are necessary for bacterial survival, and an oxidative mode involving chemically reactive molecules containing oxygen. It is the oxidative mode of defense that is defective in patients with CGD.

Building on their previous research findings showing that a protein called “olfactomedin-4” (Olfm4) hinders white blood cells’ ability to eradicate bacteria, the researchers deleted the Olfm4 gene in a mouse model of CGD and evaluated the impact of this deletion on host defense against S. aureus and A. fumigatus, both of which are common causes of infections in people with CGD. White blood cells obtained from mice lacking Olfm4 protein showed increased ability to kill S. aureus compared to white blood cells having Olfm4. Likewise, when mice lacking Olfm4 were exposed to S. aureus for six hours, they killed significantly more bacteria than mice with Olfm4.

Next, the investigators examined whether deletion of Olfm4 in CGD mice enhanced host defense against infections of S. aureus and A. fumigatus as measured by survival over a two week testing period. When infected with S. aureus, all CGD mice with Olfm4 died within ive days, while the majority (approximately 85 percent) of CGD mice without Olfm4 survived the two-week testing period. Notably, approximately 75 percent of normal mice with Olfm4 died within eight days. When infected with A. fumigatus, all CGD mice died within nine days, whether or not they had Olfm4. In contrast, all normal mice with or without Olfm4 survived the two week testing period following A. fumigatus infection. These results show that Olfm4 deletion can enhance host defense against S. aureus, but not A. fumigatus, in CGD mice. Future studies are needed to determine the role of Olfm4 in human white blood cells and could lead to the development of a therapeutic inhibitor of Olfm4 activity to boost human defense against infection.


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