Identification of genes essential for survival of hypervirulent Kleb. pneumoniae

描述（由申请人提供）：在过去十年中出现了一种新的，高毒力肺炎克雷伯菌（hvKP）的临床变体。最初的报告来自“环太平洋地区”，但最近hvKP在美国、加拿大、欧洲、以色列、澳大利亚、南非和其他地方都有报道。首先，hvKP引起的感染与传统的“经典”肺炎克雷伯菌（cKP）引起的感染的特征和区别在于：1)表现为社区获得性肝脓肿，2)影响没有肝胆疾病史的患者，3)11-80%的病例（例如眼睛、中枢神经系统（CNS）等）有转移性扩散的倾向。最近，hvKP也被描述为引起各种严重的肝外脓肿/感染。hvKP与死亡率显著相关，根据不同的研究，死亡率在3-32%之间。转移性扩散的幸存者经常遭受灾难性的发病率，如视力丧失和神经系统后遗症。从临床角度来看，hvKP具有肠道革兰氏阴性杆菌（GNB）的新特征。转移性传播在某些革兰氏阳性病原体（如葡萄球菌和链球菌）中很常见，但在肠内GNB（如大肠杆菌和cKP）中并不常见。人们对这种变化的基础知之甚少。本提案的目标之一是通过确定导致其高毒力的hvKP的新的或未被认识的致病特征来填补这一知识空白。

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. PUBLIC HEALTH RELEVANCE: A new, hypervirulent clinical variant of Klebsiella pneumoniae (hvKP) has emerged over the last decade that is distinguished from traditional infections due to "classical" K. pneumoniae (cKP) by presenting as community-acquired hepatic and extraheptatic abscesses and a propensity for causing metastatic spread to distant sites (e.g. eyes, central nervous system (CNS), & others); a highly unusual feature for Gram-negative bacilli. Further, some cases of infection due to hvKP have been caused by multi-drug resistant (MDR) strains, a trend that will undoubtedly increase making treatment challenging. Therefore, the goal of this project is fill critical knowledge gaps on the biology of hvKP by identifying and initially characterizing hvKP-specific novel/unrecognized genes that contribute to its in vivo growth/survival; information required to logically combat this emerging pathogen.