Identification of genes essential for survival of hypervirulent Kleb. pneumoniae

鉴定高毒力克雷布生存所必需的基因。

• 批准号: 8046754
• 负责人: THOMAS A RUSSO
• 金额: $ 23.78万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046754
• 关键词: Abscess; Acinetobacter baumannii; Affect; Antibiotics; Ascites; Asians; Australia; Bacillus (bacterium); Biology; Blindness; Canada; Characteristics; Clinical; Communities; Computer Simulation; Data; Disease; Distant; Enteral; Escherichia coli; Ethics; Europe; Extrahepatic; Eye; Fascia; Foundations; Fright; Genes; Genomics; Genotype; Goals; Growth; Hepatic; Hepatobiliary; Human; In Vitro; Infection; Israel; Joints; Kidney; Klebsiella pneumonia bacterium; Knowledge; Liver Abscess; Lung; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Muscle; Neuraxis; Neurologic; Outcome; Pathogenicity; Patients; Phenotype; Pleura; Pneumonia; Positioning Attribute; Prevalence; Prostate; Proteins; Recording of previous events; Reporting; Resistance; Serotyping; Serum; Site; Skin; South Africa; Spleen; Staphylococcus aureus; Survivors; United States; Variant; Virulence; Virulence Factors; Virulent; Work; base; beta-Lactamase; bone; combat; diabetic; discount; experience; in vivo; methicillin resistant Staphylococcus aureus; mortality; novel; pathogen; pathogenic Escherichia coli; resistant strain; soft tissue; trait; trend

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.

描述（由申请人提供）：在过去十年中出现了一种新的肺炎克雷伯菌（hvKP）高毒力临床变异株。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、南非和其他地方也有报道。首先，由于hvKP感染的特点，并从传统的感染，由于“经典”的K。肺炎克雷伯氏菌（cKP）：1）表现为社区获得性肝脓肿，2）影响缺乏肝胆疾病史的患者，3）在11-80%的病例中（例如眼睛，中枢神经系统（CNS）等）有导致远处转移性扩散的倾向。最近，hvKP也被描述为引起各种严重的肝外脓肿/感染。hvKP与显着的死亡率相关，根据研究的不同，死亡率范围为3-32%。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具有肠革兰氏阴性杆菌（GNB）的新特征。某些革兰氏阳性病原体（如葡萄球菌和链球菌）的转移性扩散很常见，但肠GNB（如大肠杆菌）并不常见。coli和cKP）。人们对这种变化的基础知之甚少。该提案的目标之一是通过鉴定导致其高毒力的hvKP的新的或未被识别的致病性状来填补这一知识空白。 使已经具有挑战性的临床情况更加复杂的是最近K的倾向。肺炎变得多重耐药（MDR），包括获得超广谱β-内酰胺酶和碳青霉烯酶。已经描述了一些由MDR菌株引起的hvKP感染病例，正如预期的那样，治疗不当的结局更糟。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。hvKP中的高毒力和MDR的融合有可能产生“后抗生素”情景;类似于对耐甲氧西林金黄色葡萄球菌（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至关重要。一种新的和有效的方法是用来确定新的或未识别的毒力因子，是特定的hvKP和肠外生长/生存在体外和体内是必不可少的。随后，这些毒力因子将进行初步表征。这些数据将是重要和独特的，并将为理解这种新的和可怕的临床变异的生物学奠定基础。 公共卫生关系：在过去的十年中，出现了一种新的、高毒力的肺炎克雷伯氏菌临床变异株（hvKP），它与传统的肺炎克雷伯氏菌感染不同。肺炎（cKP），表现为社区获得性肝和肝外脓肿，并倾向于导致转移性扩散到远处部位（例如眼睛、中枢神经系统（CNS）和其他）;这是革兰氏阴性杆菌的一个非常罕见的特征。此外，一些由hvKP引起的感染病例是由多药耐药（MDR）菌株引起的，这一趋势无疑将增加治疗的挑战性。因此，本项目的目标是通过识别和初步表征有助于其体内生长/存活的hvKP特异性新/未识别基因，填补hvKP生物学的关键知识空白;逻辑上对抗这种新兴病原体所需的信息。