Infections caused by both methicillin resistant (MRSA) and susceptible (MSSA) forms of Staphylococcus aureus are more frequent and severe in people with diabetes than in healthy individuals and represent a leading cause of hospitalization. A hallmark of S. aureus skin infection is the formation of an abscess that is formed by live and necrotic neutrophils, bacteria, cell debris and a capsule of fibrin/collagen. Abscess formation must be tightly regulated to prevent microbial dissemination. Since the early 1900?s, it has been shown that phagocytes from people with diabetes are unable to ingest and kill bacteria, which created the paradigm that diabetes leads to immunosuppression. Here, we will take our current knowledge in host defense and diabetes in a different direction. We speculated that increased susceptibility to infection is due to an uncontrolled inflammatory response that cause skin damage and prevents bacterial elimination. Our surprisingly published and preliminary data suggest that enhanced lesion size and bacterial load in the skin of MRSA-infected diabetic mice correlated with exaggerated nonproductive neutrophil migration to the site of infection and a lack of well-defined abscesses. Our central hypothesis is that hyperglycemia induces an enhanced and persistent inflammatory response to S. aureus skin infection due to inefficient efferocytosis. We propose the following specific aims: 1) Determine the role of high glucose in poor abscess formation and inadequate host defense during S. aureus skin infection in diabetic mice. 2) Assess the mechanisms involved in cell death elimination and exaggerated inflammatory response during S. aureus skin infection in diabetic mice. We will employ a series of pharmacologic and genetic approaches, associated with imaging mass spectrometry (IMS), immunohistochemistry and flow cytometry to unveil novel interactions among macrophages and the production of inflammatory molecules that might dictate phagocyte recruitment and abscess formation in both diabetic and nondiabetic mice. After this project, we expect to have delineated a framework for further dissecting the dynamics of poor skin host defense that may improve our understanding of innate immune responses and their potential for therapeutic manipulation in diabetes. We should then be positioned to take this work further in both basic and translational directions.

Public Health Relevance

Uncontrolled high blood sugar in diabetic people increases their risk of various inflammation-related conditions. People with diabetes are more likely to be infected by Staphylococcus aureus infection, but the reasons for this enhanced susceptibility to infection are unclear. This project will provide new fundamental knowledge regarding the regulation of inflammation, which could contribute to the development of new therapeutic strategies, and will also lead to further work in areas of research beyond diabetes and infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Huntley, Clayton C
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Vanderbilt University Medical Center
United States
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