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Nosocomial infections caused by gram-negative pathogens such as Acinetobacter baumannii have become amajor challenge in the treatment of immunocompromised individuals and patients with traumatic injuries. Theseinfections include ventilator-associated pneumonia, catheter-related urinary tract infections and non-healingwound infections that can ultimately lead to sepsis. Of significant concern is the increasing frequency of life-threatening infections caused by drug resistant A baumannii, reinforcing the need for new therapeuticapproaches. Therapeutics directed against virulence factors or in vivo fitness that are unaffected by existingmechanisms of resistance are appealing treatment options. However, while much research has focused on themechanisms of antibiotic resistance and the epidemiology of A. baumannii, our understanding of A. baumanniipathogenesis is lagging, and little is known about the contribution of secreted proteins to the ability of A.baumannii to survive and cause disease in the human host. The impact of extracellular proteases on virulencehas been demonstrated for many bacterial pathogens, and, therefore, in this application we will examine thevirulence potential of a recently discovered extracellular protease, CpaA. This unique, Adamalysin-likemetalloprotease is delivered to the extracellular environment by the type II secretion system (T2SS). The T2SSenhances in vivo fitness of A. baumannii in a murine model for bacteremia, in part, due to extracellular secretionof CpaA. Our preliminary data demonstrate that CpaA rapidly inhibits the contact activation pathway of bloodcoagulation in both human and murine plasma by specifically cleaving and inactivating factor XII. This proposalaims to biochemically characterize CpaA and determine how targeting of factor XII by CpaA facilitates survivalof A. baumannii in vivo. These studies will advance our understanding of A. baumannii pathogenesis, especiallywith respect to its evasion of innate host defense mechanisms within the vascular system. Our study also hassignificant translational implications that ultimately may lead to the development of new therapeutic orpreventative strategies to limit the morbidity and mortality associated with A. baumannii infections.

Sandkvist, Maria
University of Michigan - Ann Arbor
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