Role of PARP-1 in Salmonella Pathogenesis

描述(由申请人提供)：沙门氏菌是一种潜在的生物恐怖主义病原体(NIAID B类优先病原体)，可导致危及生命的系统性感染。我们的目的是了解聚腺苷二磷酸核糖聚合酶-1(PARP-1)在沙门氏菌发病机制中的作用。 最近，PARP-1缺陷(PARP-1-/-)小鼠和组织被证明对炎性刺激具有抵抗力。我们的初步研究表明，PARP-1-/-小鼠对鼠伤寒沙门氏菌诱导的感染性休克具有抵抗力，这表明PARP-1在沙门氏菌的致病机制中起着重要作用。此外，已知PARP-1介导炎症性坏死性细胞死亡，并调节炎症相关基因表达所需的各种转录因子。这些事件可能对沙门氏菌感染的结果至关重要。巨噬细胞的先天免疫反应是抵御感染的第一道防线，因此是决定疾病结局的关键参数。然而，PARP-1在鼠伤寒沙门氏菌感染的巨噬细胞天然免疫反应中的作用目前尚不清楚。 我们的假设是：(A)PARP-1活性在沙门氏菌感染过程中被诱导，进而介导caspase-1依赖的巨噬细胞死亡，以及(B)PARP-1调节鼠伤寒沙门氏菌诱导的巨噬细胞特异性转录因子和相关炎症基因的表达。我们的目的是(1)确定PARP-1在鼠伤寒沙门氏菌感染的巨噬细胞中的作用以及在鼠伤寒沙门氏菌诱导的caspase-1依赖的巨噬细胞死亡中的作用；(2)确定PARP-1在鼠伤寒沙门氏菌内毒素激活的巨噬细胞中调节的特异性转录因子和促炎基因。 R21机制：我们的项目处于开发的早期阶段，我们的初步数据有限。R21机制将使我们能够收集有关PARP-1在鼠伤寒沙门氏菌感染的巨噬细胞的天然免疫反应中所起作用的关键信息。这些初步研究对于未来的R01将是至关重要的，以确定PARP-1在沙门氏菌发病中的确切作用，并开发预防和治疗感染的方法。

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. 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. 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. 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.