| dc.description.abstract | Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections in health care settings and those with diabetes worldwide. There is an unmet clinical need to develop new immunotherapeutic strategies to treat these antibiotic-resistant infections. MRSA skin infections are characterized by the formation of a neutrophilic abscess that is the hallmark of pyogenic infections to prevent bacterial spread to deeper tissues. However, the events and factors that drive ideal host defense during these infections remain to be fully elucidated. Here we examined the role of the lipid mediator prostaglandin E2 and the protein SOCS-1 and their impact on host defense during MRSA skin infection in both hyperglycemic and euglycemic mice.
We have previously shown that hyperglycemic mice are unable to control MRSA skin infection, and exhibit higher bacterial load, lesion size, and poor abscess formation. Our data indicate that while PGE2 production is lower, SOCS-1 expression is higher in the skin of hyperglycemic mice during skin infection, correlating with poor infection outcomes. Restoration of PGE2 signaling via treatment with the PGE analog misoprostol improved infection outcomes in hyperglycemic mice and was associated with enhanced CXC chemokine secretion and CXCR2+ monocyte and neutrophil recruitment. Pharmacological or genetic inhibition of SOCS-1 in both control and hyperglycemic mice also decreased lesion size and improved bacterial clearance in the skin, resulting in better infection outcomes. Inhibiting SOCS-1 during infection increased the production of type I and type II interferons, with an anti-type II interferon receptor blocking antibody ablating the therapeutic benefit of SOCS-1 inhibition. Furthermore, SOCS-1 inhibition improved phagocytosis and intracellular bacterial killing in macrophages isolated from hyperglycemic and control mice. Overall, these data demonstrate that the balance between PGE2 production and SOCS-1 expression dictates skin host defense in both hyperglycemic and euglycemic patients. Furthermore, our work highlights a novel drug repurposing strategy to treat antibiotic-resistant pathogens in hyperglycemic patients. | |
