Acinetobacter virulence and host innunopathogenesis

性状（由申请方提供）：鲍曼不动杆菌是美国（US）和全世界最高度耐药的微生物之一。高达70%的A。鲍曼不动杆菌临床分离株现在具有广泛的耐药性（XDR;即对除粘菌素或替加环素之外的所有抗生素具有耐药性），反映了自2000年以来>15倍的增加。此外，泛耐药（PDR）A引起的感染。鲍曼不动杆菌（对所有可用的抗生素都有耐药性）已经出现，并且由于缺乏治疗A.鲍曼不动杆菌。 发展新的防治策略。鲍曼不动杆菌感染需要了解宿主-微生物相互作用。然而，微生物和宿主因素使A.鲍曼不动杆菌引起严重感染的定义尚不明确。新的数据证实了临床分离的A.鲍曼不动杆菌（见初步数据）。然而，组织细菌负荷在感染或多或少毒性（即致死性与非致死性）菌株的小鼠之间没有差异，并且通过组织病理学，在任何小鼠中均未发现组织微膨胀或细菌入侵。相反，在血管内发现微生物，并存在毛细血管炎，与脂多糖（LPS）介导的全身性脓毒症诱导一致。 以前认为TLR 4是宿主防御A.与其它革兰氏阴性杆菌一样，TLR 4缺陷型小鼠在非致死性鲍曼不动杆菌模型中比野生型小鼠更慢地清除细菌负荷。鲍曼不动杆菌感染支持主流科学观点的是初步数据，表明TLR 4是反保护性的，因为 全身感染A.与野生型对照小鼠的100%死亡率相比，鲍曼不动杆菌没有导致TLR 4突变小鼠死亡。最后，从更毒力菌株的LPS更有力地诱导TLR 4在体外激活比从毒力较低的菌株。因此，假设LPS的TLR 4激活能力是区分A.鲍曼不动杆菌。还假设，比较基因组学，重点是LPS合成途径，将确定改变的遗传谱在较高与较低的毒力菌株。基于这些结果，具体的目的是：1）阐明感染期间体内LPS活性、毒力和炎症严重程度之间的关系;和2）确定与A.鲍曼不动杆菌。 鲍曼不动杆菌已成为医院感染最具耐药性的常见原因之一。迄今为止，很少有致病机制的研究已经进行，微生物的毒力因子和宿主因子的毒力仍然未知。本申请基于新的观察结果，即TLR 4对A.体内鲍曼不动杆菌感染，并将确定关键的LPS-毒力关系 在不同毒力的菌株之间。目前的建议将为未来的R 01奠定基础，重点是解剖体内不同感染部位的毒力分子机制。

DESCRIPTION (provided by applicant): Acinetobacter baumannii is one of the most highly antibiotic-resistant organisms in the United States (US) and throughout the world. Up to 70% of A. baumannii clinical isolates are now extensively drug resistant (XDR; i.e. resistant to all antibiotics except colistin or tigecycline), reflecting a >15-fold increase since 2000. Furthermore infections caused by pandrug-resistant (PDR) A. baumannii (resistant to all available antibiotics) are already being seen, and will continue to increase given the lack of new drugs in the pipeline to treat A. baumannii. Development of new prevention and treatment strategies for A. baumannii infections requires an understanding of host-microbe interactions. Yet microbial and host factors that enable A. baumannii to cause severe infection remain poorly defined. New data confirm diversity of virulence in clinical isolates of A. baumannii (see Preliminary Data). Yet tissue bacterial burden did not differ between mice infected with the more or less virulent (i.e. lethal vs. non-lethal) strains, and by histopathology no tissue micro-abscesses or bacterial invasion was found in any mice. Rather, organisms were found intravascularly and capillaritis was present, consistent with lipopolysaccharide (LPS)-mediated induction of systemic sepsis. TLR4 was previously believed to be required for host defense against A. baumannii, as for other Gram negative bacilli, because TLR4-deficient mice more slowly cleared bacterial burden compared to wild type mice in non-lethal models of A. baumannii infection. Challenging the prevailing scientific opinion are Preliminary Data indicating that TLR4 is anti-protective, because systemic infection with virulent A. baumannii resulted in no mortality of TLR4-mutant mice vs. 100% mortality of wild-type control mice. Finally, LPS from the more virulent strain more potently induced TLR4 activation in vitro than from the less virulent strain. Hence, it is hypothesized that TLR4-activation potency of LPS is a key factor that distinguishes more and less virulent strains of A. baumannii. It is also hypothesized that comparative genomics, focusing on LPS synthetic pathways, will identify altered genetic profiles in higher vs. lower virulence strains. Based on these results, the Specific Aims are: 1) To elucidate relationships between LPS activity, virulence, and severity of inflammation in vivo during infection; and 2) To define molecular genetic signatures linked to increasing or decreasing virulence in clinical isolates of A. baumannii. Acinetobacter baumannii has emerged as one of the most antibiotic-resistant, common causes of nosocomial infections. To date, very little pathogenesis research has been conducted, and microbial virulence factors and host factors contributing to virulence remain unknown. The current application is based on the novel observation that TLR4 is anti-protective against A. baumannii infection in vivo, and will define key LPS- virulence relationships across strains with diverse virulence. The current proposal will lay the groundwork for a future R01 focused on dissecting the molecular mechanisms of virulence in vivo at different sites of infection.