Mesureur Jennifer, Feliciano Joana R, Wagner Nelly, Gomes Margarida C, Zhang Lili, Blanco-Gonzalez Monica, van der Vaart Michiel, O'Callaghan David, Meijer Annemarie H, Vergunst Annette C
VBMI, INSERM, Univ. Montpellier, Nîmes, France.
Institute of Biology Leiden, Leiden University, Leiden, The Netherlands.
PLoS Pathog. 2017 Jun 26;13(6):e1006437. doi: 10.1371/journal.ppat.1006437. eCollection 2017 Jun.
Bacteria of the Burkholderia cepacia complex (Bcc) can cause devastating pulmonary infections in cystic fibrosis (CF) patients, yet the precise mechanisms underlying inflammation, recurrent exacerbations and transition from chronic stages to acute infection and septicemia are not known. Bcc bacteria are generally believed to have a predominant extracellular biofilm life style in infected CF lungs, similar to Pseudomonas aeruginosa, but this has been challenged by clinical observations which show Bcc bacteria predominantly in macrophages. More recently, Bcc bacteria have emerged in nosocomial infections of patients hospitalized for reasons unrelated to CF. Research has abundantly shown that Bcc bacteria can survive and replicate in mammalian cells in vitro, yet the importance of an intracellular life style during infection in humans is unknown. Here we studied the contribution of innate immune cell types to fatal pro-inflammatory infection caused by B. cenocepacia using zebrafish larvae. In strong contrast to the usual protective role for macrophages against microbes, our results show that these phagocytes significantly worsen disease outcome. We provide new insight that macrophages are critical for multiplication of B. cenocepacia in the host and for development of a fatal, pro-inflammatory response that partially depends on Il1-signalling. In contrast, neutrophils did not significantly contribute to disease outcome. In subcutaneous infections that are dominated by neutrophil-driven phagocytosis, the absence of a functional NADPH oxidase complex resulted in a small but measurably higher increase in bacterial growth suggesting the oxidative burst helps limit bacterial multiplication; however, neutrophils were unable to clear the bacteria. We suggest that paradigm-changing approaches are needed for development of novel antimicrobials to efficiently disarm intracellular bacteria of this group of highly persistent, opportunistic pathogens.
洋葱伯克霍尔德菌复合体（Bcc）细菌可在囊性纤维化（CF）患者中引发毁灭性的肺部感染，但炎症、反复病情加重以及从慢性阶段转变为急性感染和败血症的精确机制尚不清楚。一般认为，Bcc细菌在受感染的CF肺部主要具有细胞外生物膜生活方式，类似于铜绿假单胞菌，但这一观点受到临床观察结果的挑战，临床观察显示Bcc细菌主要存在于巨噬细胞中。最近，Bcc细菌已出现在因与CF无关的原因住院患者的医院感染中。大量研究表明，Bcc细菌可在体外哺乳动物细胞中存活和复制，但在人类感染期间细胞内生活方式的重要性尚不清楚。在这里，我们使用斑马鱼幼虫研究了先天性免疫细胞类型对由洋葱伯克霍尔德菌（B. cenocepacia）引起的致命性促炎性感染的作用。与巨噬细胞通常对微生物的保护作用形成强烈对比的是，我们的结果表明这些吞噬细胞会显著恶化疾病结局。我们提供了新的见解，即巨噬细胞对于洋葱伯克霍尔德菌在宿主体内的增殖以及部分依赖Il1信号传导的致命性促炎性反应的发展至关重要。相比之下，中性粒细胞对疾病结局的贡献不显著。在以中性粒细胞驱动的吞噬作用为主的皮下感染中，功能性NADPH氧化酶复合体的缺失导致细菌生长有小幅但可测量的更高增加，这表明氧化爆发有助于限制细菌增殖；然而，中性粒细胞无法清除细菌。我们认为，需要采用改变范式的方法来开发新型抗菌药物，以有效消除这组高度持久的机会性病原体的细胞内细菌。
