Friday, November 22, 2024
11/22/2024
Project Summary The emergence of bacterial drug resistance, especially in hospital settings, represents the next great challenge in healthcare. Serratia marcescens, the Gram-negative bacterial pathogen with intrinsic resistance to several classes of antibiotics, can cause infections with severe outcomes affecting multiple body sites. This bacterium is also associated with complications of peritoneal dialysis (PD) in patients with kidney failure. Importantly, Serratia-associated peritonitis accompanied by massive neutrophil infiltration was shown to have the highest nonresolution rate among episodes caused by Gram-negative bacteria, leading either to the death of the PD patient, or catheter removal and transfer to hemodialysis. The progress in our understanding of S. marcescens infections is hampered by the lack of reliable preclinical model, which represents a critical barrier to progress in the field. The current knowledge of strategies used by this opportunistic pathogen to colonize the mammalian host and to evade the immune response is not complete, and only a handful of virulence factors were identified to date. S. marcescens is known to secrete an array of hydrolytic enzymes, including sugar non-specific endonuclease; however, the biological role of this enzyme during infection has not been evaluated. In this proposal, we seek to establish a murine model to study the S. marcescens dynamic spread during intraperitoneal infection and to test a hypothesis that an extracellular S. marcescens enzyme nuclease plays a key role in bacterial escape from neutrophil extracellular traps (NETs) in this niche. In Aim 1 we will characterize the bioluminescent S. marcescens spread following intraperitoneal infection using in vivo imaging. In Aim 2 we will first evaluate the S. marcescens extracellular nuclease potential to degrade NETs in cultures of neutrophil-like cells, followed by infection study to determine the biological role of this enzyme in vivo. This proposal will advance current understanding of Serratia pathogenesis and provide insight into the bacterium’s strategy to avoid neutrophil-mediated clearance. Altogether, our experiments will establish a blueprint for future studies of other nuclease-producing pathogenic bacteria.
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