Chronic wounds affect millions of people worldwide and constitute a major, often neglected, healthcare problem. Individuals with diabetes, one of the largest threats to health in the 21st century, are prone to develop chronic wounds, which account for 84% of all amputations in this patient population with a 5-year mortality rate of about 50% after amputation. In diabetic wounds, bacteria often colonize the damaged tissue thereby triggering and perpetuating an already non-resolving inflammatory state that is ineffective at clearing the infection. The opportunistic pathogen Enterococcus faecalis is commonly isolated from infected wounds and, depending on the study population and identification method, can be isolated in 15 to 35% of diabetic chronic wounds. It is well established that virtually all bacteria require the transition metals iron (Fe) and manganese (Mn) for a multitude of processes, ranging from virulence and oxidative stress tolerance to primary metabolism. In particular, efficient acquisition of Fe and Mn by bacterial pathogens is especially important during infection as these metals are found in tight association with hemoproteins and metalloproteins that rapidly chelate metals from tissues, a process termed nutritional immunity. A pathogenic link between perturbations in metal homeostasis and diabetes have been demonstrated for quite some time, but whether this is a contributing factor to chronic wound development is yet to be determined. In this application, our working hypotheses are that bacterial metal uptake systems play a major role in wound infection and that patients with uncontrolled diabetes are unable to maintain metal homeostasis at the wound site, which negatively affects the healing process facilitating bacterial colonization and persistence. Using an established wound infection model in wild- type (C57BL/6) mice and in a well-characterized mouse model of type 2 diabetes (db/db mice), the goals of this application are to elucidate the role of Fe and Mn transport systems in E. faecalis pathogenesis, and uncover the role of local metal homeostasis on immunological processes associated with wound healing and infection. These findings are expected to have broad implications and can facilitate the design of new therapeutic approaches to prevent infection and treat chronically infected wounds. Moreover, how the condition of diabetes affects these host-pathogen interactions will be elucidated.
Individuals with diabetes often develop chronic wounds that can be infected by opportunistic bacteria such as Enterococcus faecalis. Bacteria, including E. faecalis, require certain nutrients in the form of metals for many processes, which allow them to infect their host. In this project, we propose to evaluate the role of two essential biometals, iron and manganese, in E. faecalis survival and infectivity as well as host responses associated with wound healing, under the condition of type 2 diabetes.
