Phase-variable gene expression in Pseudomonas aeruginosa

描述（由申请方提供）：铜绿假单胞菌是人类重要的机会致病菌，是囊性纤维化（CF）患者发病和死亡的主要原因。在慢性感染的CF肺中，微生物以生物膜的形式存在，生物膜是包裹在聚合物基质中的表面附着的细菌群落。这种生物膜生长模式增强了铜绿假单胞菌对抗生素的耐药性，并有助于逃避宿主免疫应答。 在铜绿假单胞菌的生物膜形成中起重要作用的那些基因中突出的是cupA基因，其编码促进表面附着的推定菌毛结构的组分。我们已经发现，MvaT，一种最近在铜绿假单胞菌中鉴定为毒力基因表达的全局调节因子的蛋白，控制cupA菌毛基因簇的相位可变（即ON/OFF）表达。拟议的研究将确定MvaT如何发挥这种控制作用。我们最近的研究结果也牵连Rho，转录终止因子，在这同一过程中。因此，我们建议探索MvaT和Rho协同作用以实现有效抑制相位可变cupA基因表达的可能性。此外，我们将试图阐明相变量cupA基因的表达（第一种记录在铜绿假单胞菌）实际发生的机制。 我们预计，这些研究将阐明MvaT控制cupA基因表达的机制，并通过扩展，其他MvaT靶基因，有助于毒力。我们进一步预期，这些研究也将揭示铜绿假单胞菌中相位可变基因表达背后的分子基础。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an important opportunistic pathogen of humans that is notorious for being the principal cause of morbidity and mortality in Cystic Fibrosis (CF) patients. In the chronically infected CF lung the organism persists as a biofilm-a surface attached community of bacteria encased in a polymeric matrix. This biofilm mode of growth augments the resistance of P. aeruginosa to antibiotics and facilitates evasion of the host immune response. Prominent amongst those genes that play an important role in biofilm formation in P. aeruginosa are the cupA genes, which encode components of a putative fimbrial structure that facilitates surface- attachment. We have found that MvaT, a protein recently identified in P. aeruginosa as a global regulator of virulence gene expression, controls the phase-variable (i.e. ON/OFF) expression of the cupA fimbrial gene cluster. The proposed studies will determine how MvaT exerts this control. Our recent findings also implicate Rho, a transcription termination factor, in this same process. We therefore propose to explore the possibility that MvaT and Rho function synergistically to achieve efficient repression of phase-variable cupA gene expression. Moreover, we will attempt to elucidate the mechanism by which phase-variable cupA gene expression (the first of its kind documented in P. aeruginosa) actually occurs. We anticipate that these studies will illuminate the mechanism by which MvaT controls the expression of the cupA genes and, by extension, other MvaT-target genes that contribute to virulence. We anticipate further that these studies will also shed light on the molecular basis behind phase-variable gene expression in P. aeruginosa.