Host Fate is Rapidly Determined by Innate Effector-Microbial Interactions During Acinetobacter baumannii Bacteremia
Host Fate is Rapidly Determined by Innate Effector-Microbial Interactions During Acinetobacter baumannii Bacteremia
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DOI：
10.1093/infdis/jiu593
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发表时间：
2015-04-15
影响因子：
6.4
通讯作者：
Spellberg, Brad
中科院分区：
文献类型：
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作者：
Bruhn, Kevin W.;Pantapalangkoor, Paul;Spellberg, Brad
背景资料。鲍曼不动杆菌是最耐药的病原菌之一。明确致病机制是实现新的治疗方法的关键。我们研究了鲍曼不动杆菌临床分离株在小鼠菌血症期间的不同毒力差异，以阐明驱动结果的宿主-微生物相互作用。我们确定了超强毒力菌株，这些菌株在低剂量静脉接种时是致命的，并且在早期和持续的血液中获得了非常高的细菌密度。强毒菌株在低接种量时不致死，在高接种量2.5倍时致死。最后，相对无毒(低毒)的菌株在20倍的高接种量时是非致死的，并在早期时间点被有效清除。体内毒力与体外对补体和巨噬细胞摄取的抵抗力相关。补体、巨噬细胞和中性粒细胞的耗尽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，所有3种效应机制的破坏使早期的细菌密度与超强毒株相似，使感染100%致死。鲍曼不动杆菌的致死性取决于不同的阶段。对早期先天效应物耐药的菌株能够建立非常高的早期细菌血液密度，随后持续的菌血症导致Toll样受体4介导的炎症和致死性。这些结果对开发调节宿主-微生物相互作用的治疗方法的翻译工作具有重要意义。
Background. Acinetobacter baumannii is one of the most antibiotic-resistant pathogens. Defining mechanisms driving pathogenesis is critical to enable new therapeutic approaches.Methods. We studied virulence differences across a diverse panel of A. baumannii clinical isolates during murine bacteremia to elucidate host-microbe interactions that drive outcome.Results. 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.Conclusions. 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.