Department of Virology, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Internal Medicine, Faculty of Medicine and Life Sciences, Tampere University Hospital, University of Tampere, Tampere, Finland.
Front Immunol. 2018 Sep 18;9:2098. doi: 10.3389/fimmu.2018.02098. eCollection 2018.
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection . These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.
汉坦病毒可引起人类肾综合征出血热（HFRS）和汉坦病毒心肺综合征（HCPS）。这两种疾病都被认为是免疫介导的，但确切的病理机制仍知之甚少。中性粒细胞被认为是抵御入侵微生物的第一道防线，但人们对其在病毒感染中的作用仍知之甚少。我们希望使用从感染普马拉汉坦病毒（PUUV）的患者中获得的血液和组织样本，研究中性粒细胞在 HFRS 中的作用。我们发现，中性粒细胞活化产物髓过氧化物酶和中性粒细胞弹性蛋白酶，以及白细胞介素-8（人类主要的中性粒细胞趋化因子），在急性 PUUV-HFRS 患者的血液中显著升高，并与肾功能障碍呈正相关，肾功能障碍是 HFRS 的主要临床发现。这些标志物主要定位于 PUUV-HFRS 患者肾脏的肾小管间质空间，表明中性粒细胞活化可能是针对汉坦病毒的一般免疫反应的一个组成部分。我们还观察到，在疾病的急性阶段，循环细胞外组蛋白水平升高，支持先前在 PUUV-HFRS 中发现的中性粒细胞细胞外陷阱形成的发现。从机制上讲，我们没有发现直接的 PUUV 介导的中性粒细胞活化的证据，而是主要的血液微血管内皮细胞获得了促炎表型，并在受到 PUUV 感染时促进中性粒细胞脱颗粒。这些结果表明，中性粒细胞被感染的内皮细胞激活，并可能导致决定 HFRS 严重程度的肾脏病理。
