Programmed cell death in P. aeruginosa

 描述（由申请方提供）：程序性细胞死亡（PCD）是指由遗传编码程序导致的细胞自杀。虽然在多细胞生物中广泛存在，但细菌中PCD的记录相对较少。在细菌中，PCD似乎在限制噬菌体的传播和生物膜的形成中起作用。我们已经发现了一个潜在的PCD途径的致病菌铜绿假单胞菌。这种PCD途径可以在响应DNA损伤的细胞亚群中被激活，并在肺部感染模型中促进铜绿假单胞菌的毒力。DNA损伤导致我们称为AlpR的基本转录调节因子的裂解，其通过alpA基因的去抑制而导致细胞裂解程序的激活。反过来，Alpa积极地 调节alpBCDE裂解基因的表达。接种的细胞裂解可以提供营养物或释放毒素或其他细菌因子，其可能促进群体中剩余的铜绿假单胞菌细胞的肺定殖。在目的1中，我们提出确定AlpR调节的alpBCDE基因如何影响细胞裂解。在目标2中，我们提出确定AlpA如何积极控制靶基因的表达，并确定可能受AlpA控制的PCD途径的其他组成部分。最后，在目标3中，我们将开始确定群体中铜绿假单胞菌细胞亚群的PCD如何增强急性肺炎模型中的毒力。通过这些研究，我们希望阐明病原体在感染过程中如何利用PCD作为生存促进策略。此外，我们的研究结果可能对使用损伤DNA的抗生素治疗铜绿假单胞菌感染有影响。

 DESCRIPTION (provided by applicant): Programmed cell death (PCD) refers to cell suicide that results from a genetically encoded program. Although widespread among multicellular organisms, there are relatively few documented instances of PCD in bacteria. In bacteria, PCD appears to have roles in limiting the spread of bacteriophage, and in the formation of biofilms. We have uncovered a potential PCD pathway in the pathogenic bacterium Pseudomonas aeruginosa. This PCD pathway can be activated in a subset of cells in response to DNA damage and promotes the virulence of P. aeruginosa in a lung infection model. DNA damage results in cleavage of an essential transcription regulator that we call AlpR, which leads to the activation of a cell lysis program via the de-repression of the alpA gene. In turn, AlpA positively regulates expression of the alpBCDE lysis genes. The cell lysis that ensues could provide nutrients or liberate toxins or other bacterial factors that might facilitate lung colonization by he remaining P. aeruginosa cells in the population. In Aim 1 we propose to determine how the AlpR-regulated alpBCDE genes influence cell lysis. In Aim 2 we propose to determine how AlpA positively controls the expression of target genes and identify an additional component of the PCD pathway that may be under the control of AlpA. Finally, in Aim 3 we will begin to determine how the PCD of a subset of P. aeruginosa cells in a population enhances virulence in an acute pneumonia model. With these studies we hope to elucidate how a pathogen exploits PCD as a survival-promoting strategy during the course of an infection. Additionally, our findings may have implications for the treatment of P. aeruginosa infections with antibiotics that damage the DNA.