Role of PARP-1 in Salmonella Pathogenesis

Georgetown University, Washington DC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Salmonella, a potential bioterrorism agent (NIAID Category B Priority Pathogens), can cause life threatening systemic infections. Our objective is to understand the role of poly(ADP-ribose) polymerase-1(PARP-1) in Salmonella pathogenesis. [unreadable] [unreadable] Recently, PARP-1-deficient (PARP-1-/-) mice and tissue have been shown to be resistant to inflammatory stimuli. Our preliminary studies indicate that PARP-1-/- mice are resistant to Salmonella typhimurium induced septic shock, suggesting that PARP-1 plays an essential role in Salmonella pathogenesis. Additionally, PARP-1 is known to mediate inflammatory-type necrotic cell death and regulate various transcription factors required for the inflammation associated gene expression. These events may be crucial for the outcome of Salmonella infection. Innate immune responses of macrophages are the first-line of defense against infection and therefore a critical parameter for determining the outcome of diseases. However, the role of PARP-1 on innate immune responses of S. typhimurium infected macrophages is currently unknown. [unreadable] [unreadable] Our hypotheses are (a) PARP-1 activity is induced during Salmonella infection and in turn mediates caspase-1-dependent macrophage cell death, and (b) PARP-1 regulates S. typhimurium LPS-induced specific transcription factors and associated inflammatory gene expression in macrophages. Our Aims are to (1) determine the role of PARP-1 in S. typhimurium infected macrophages and on S. typhimurium-induced caspase-1-dependent macrophage cell death, and (2) identify specific transcription factors and proinflammatory genes regulated by PARP-1 in S. typhimurium LPS-activated macrophages. [unreadable] [unreadable] R21 Mechanism: Our project is at an early stage of development, and our preliminary data are limited. The R21 mechanism will allow us to gather critical information regarding the role of PARP-1 on innate immune responses of S. typhimurium infected macrophages. These preliminary studies will be critical for a future R01 to determine the precise role of PARP-1 on Salmonella pathogenesis and to develop methods for the prevention and treatment of infection. [unreadable] [unreadable]