Paris Daniel H, Stephan Femke, Bulder Ingrid, Wouters Diana, van der Poll Tom, Newton Paul N, Day Nicholas P J, Zeerleder Sacha
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands.
PLoS Negl Trop Dis. 2015 Aug 28;9(8):e0003990. doi: 10.1371/journal.pntd.0003990. eCollection 2015.
Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus.
细胞介导的免疫对于预防立克次体病至关重要，但中性粒细胞在这些细胞内嗜血管感染中的作用仍不清楚。本研究分析了同时患有恙虫病和鼠型斑疹伤寒的老挝患者血浆中的核小体水平、FSAP激活（核小体释放因子）以及中性粒细胞激活情况，中性粒细胞弹性蛋白酶（ELA）复合物可证明中性粒细胞激活。在急性恙虫病中，升高的核小体水平与较低的格拉斯哥昏迷评分、呼吸频率升高、黄疸和肝功能受损相关，而中性粒细胞激活与纤维蛋白溶解和高血浆IL-8水平相关，IL-8是最近确定的严重疾病和死亡率的预测指标。核小体和ELA复合物水平分别超过1040 U/ml和275 U/ml的临界值时，发生严重恙虫病的风险分别增加4.8倍和4倍。在鼠型斑疹伤寒中，核小体水平与促炎细胞因子和病程相关，而ELA复合物与炎症标志物、黄疸和呼吸频率增加密切相关。本研究发现恙虫病患者循环核小体与中性粒细胞激活之间存在强相关性，但鼠型斑疹伤寒患者不存在，这间接证明核小体可能源自中性粒细胞胞外诱捕网（NET）降解。高循环血浆核小体和ELA复合物是恙虫病发生严重并发症的独立危险因素。由于暴露在NETs上的核小体和组蛋白对内皮细胞具有高度细胞毒性且具有强烈的促凝作用，中性粒细胞衍生的核小体可能导致血管损伤、促凝状态和恙虫病病情加重，从而表明中性粒细胞激活具有有害作用。数据表明中性粒细胞激活增加与疾病进展和严重并发症相关，血浆核小体和ELA复合物水平升高是发生严重恙虫病的独立危险因素。
