Bruhn Kevin W, Pantapalangkoor Paul, Nielsen Travis, Tan Brandon, Junus Justin, Hujer Kristine M, Wright Meredith S, Bonomo Robert A, Adams Mark D, Chen Wangxue, Spellberg Brad
Department of Molecular Microbiology and Immunology.
Department of Medicine Department of Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Ohio.
J Infect Dis. 2015 Apr 15;211(8):1296-305. doi: 10.1093/infdis/jiu593. Epub 2014 Nov 5.
Acinetobacter baumannii is one of the most antibiotic-resistant pathogens. Defining mechanisms driving pathogenesis is critical to enable new therapeutic approaches.
We studied virulence differences across a diverse panel of A. baumannii clinical isolates during murine bacteremia to elucidate host-microbe interactions that drive outcome.
We identified hypervirulent strains that were lethal at low intravenous inocula and achieved very high early, and persistent, blood bacterial densities. Virulent strains were nonlethal at low inocula but lethal at 2.5-fold higher inocula. Finally, relatively avirulent (hypovirulent) strains were nonlethal at 20-fold higher inocula and were efficiently cleared by early time points. In vivo virulence correlated with in vitro resistance to complement and macrophage uptake. Depletion of complement, macrophages, and neutrophils each independently increased bacterial density of the hypovirulent strain but insufficiently to change lethality. However, disruption of all 3 effector mechanisms enabled early bacterial densities similar to hypervirulent strains, rendering infection 100% fatal.
The lethality of A. baumannii strains depends on distinct stages. Strains resistant to early innate effectors are able to establish very high early bacterial blood density, and subsequent sustained bacteremia leads to Toll-like receptor 4-mediated hyperinflammation and lethality. These results have important implications for translational efforts to develop therapies that modulate host-microbe interactions.
鲍曼不动杆菌是最具抗生素耐药性的病原体之一。明确驱动发病机制的因素对于开发新的治疗方法至关重要。
我们研究了多种鲍曼不动杆菌临床分离株在小鼠菌血症期间的毒力差异，以阐明驱动疾病转归的宿主-微生物相互作用。
我们鉴定出高毒力菌株，这些菌株在低静脉接种量时具有致死性，并在早期及之后维持非常高的血液细菌密度。毒力菌株在低接种量时无致死性，但在接种量高2.5倍时具有致死性。最后，相对无毒力（低毒力）的菌株在接种量高20倍时无致死性，并在早期被有效清除。体内毒力与体外对补体和巨噬细胞摄取的抗性相关。补体、巨噬细胞和中性粒细胞的耗竭各自独立地增加了低毒力菌株的细菌密度，但不足以改变致死率。然而，破坏所有这三种效应机制可使早期细菌密度与高毒力菌株相似，导致感染100%致死。
鲍曼不动杆菌菌株的致死性取决于不同阶段。对早期固有效应器具有抗性的菌株能够在早期建立非常高的细菌血液密度，随后持续的菌血症导致Toll样受体4介导的过度炎症反应和致死性。这些结果对于开发调节宿主-微生物相互作用的治疗方法的转化研究具有重要意义。
