Identification of genes essential for survival of hypervirulent Kleb. pneumoniae

描述(由申请人提供)：在过去的十年中，出现了一种新的、超强毒力的肺炎克雷伯菌临床变异株(HvKP)。最初的报告来自“环太平洋地区”，但最近在美国、加拿大、欧洲、以色列、澳大利亚、南非和其他地方描述了HvKP。首先，HvKP感染的特征和区别于“经典”肺炎克雷伯菌(CKP)引起的传统感染：1)表现为社区获得性肝脓肿，2)影响没有肝胆疾病病史的患者，3)11-80%的病例有转移到远处的倾向(如眼睛、中枢神经系统(CNS)等)。最近，hvKP也被描述为引起各种严重的肝外脓肿/感染。HvKP与显著的死亡率有关，根据研究，死亡率从3%到32%不等。转移的幸存者经常遭受灾难性的疾病，如视力丧失和神经后遗症。从临床角度来看，hvKP具有肠道革兰氏阴性杆菌(GNB)的新特征。对于某些革兰氏阳性病原体，如葡萄球菌和链球菌，转移性传播是常见的，但不常见的肠道GNB(例如，大肠杆菌和CKP)。人们对这一变化的基础知之甚少。这项建议的目标之一是通过确定导致其超强毒力的新的或未被识别的HvKP致病特性来填补这一知识空白。 使本已具有挑战性的临床形势雪上加霜的是最近肺炎克雷伯菌变得对多药耐药(MDR)的倾向，包括获得超广谱β-内酰胺酶和碳青霉烯类酶。已经描述了一些由耐多药菌株引起的HvKP感染病例，正如预期的那样，如果治疗不当，结果会更糟。因此，HvKP感染的管理将变得极具挑战性，发病率和死亡率将增加。在hvKP中，超强毒力和多药耐药的融合有可能造成“抗生素后”的情况；类似于人们对甲氧西林耐药金黄色葡萄球菌(MRSA)的担忧，但从未实现。因此，加强我们对这种高毒力病原体的了解是至关重要的。一种新的有效的方法被用来识别新的或未知的毒力因子，这些毒力因子是针对hvKP的，并且在体外和体内对肠外生长/生存是必不可少的。随后，这些毒力因子将进行初步鉴定。这些数据将是重要和独特的，并将为理解这种新的可怕的临床变异的生物学奠定基础。

DESCRIPTION (provided by applicant): A new, hypervirulent clinical variant of Klebsiella pneumoniae (hvKP) has emerged over the last decade. Initial reports were from the "Pacific Rim", but more recently hvKP has been described in the United States, Canada, Europe, Israel, Australia, South Africa and elsewhere. At first, infection due to hvKP was characterized and distinguished from traditional infections due to "classical" K. pneumoniae (cKP) by: 1) presenting as community-acquired hepatic abscess, 2) affecting patients lacking a history of hepatobiliary disease, and 3) a propensity for causing metastatic spread to distant sites in 11-80% of cases (e.g. eyes, central nervous system (CNS), & others). More recently, hvKP has also been described to cause a variety of serious extrahepatic abscesses/infections as well. hvKP is associated with a significant mortality rate, ranging from 3-32% depending on the study. Survivors with metastatic spread often suffer catastrophic morbidity such as loss of vision and neurologic sequelae. From a clinical perspective, hvKP possesses novel features for an enteric Gram-negative bacillus (GNB). Metastatic spread is common for certain Gram-positive pathogens such as Staph and Strep, but is uncommon enteric GNB (e.g. E. coli and cKP). The basis for this change is poorly understood. One of the goals of this proposal is to fill that knowledge gap by identifying novel or unrecognized pathogenic traits of hvKP that contribute to its hypervirulence. Compounding an already challenging clinical situation is the recent propensity of K. pneumoniae to become multi-dug resistant (MDR), including the acquisition of extended-spectrum beta-lactamases and carbapenemases. Some cases of infection due to hvKP caused by MDR-strains have already been described and as expected, outcome is worse with inappropriate treatment. As a result, management of infections due to hvKP will become extremely increasing challenging and morbidity and mortality rates will increase. The confluence of hypervirulence and MDR in hvKP has the potential to create a "post-antibiotic" scenario; similar to what was feared with methicillin resistant Staphylococcus aureus (MRSA) but was never realized. Therefore, enhancing our understanding of this highly virulent pathogen is critical. A novel and efficient approach is used to identify both new or unrecognized virulence factors that are specific for hvKP and are essential for extraintestinal growth/survival in vitro and in vivo. Subsequently these virulence factors will undergo initial characterization. These data will be important and unique, and will lay the foundation for understanding the biology of this new and frightening clinical variant.