Transmission of all known pathogenic orthohantaviruses (family Hantaviridae) usually occurs via inhalation of aerosols contaminated with viral particles derived from infected rodents and organ manifestation of infections is characterized by lung and kidney involvement. Orthohantaviruses found in Eurasia cause hemorrhagic fever with renal syndrome (HFRS) and New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS). However, cases of infection with Old World orthohantaviruses with severe pulmonary manifestations have also been observed. Therefore, human airway cells may represent initial targets for orthohantavirus infection and may also play a role in the pathogenesis of infections with Eurasian orthohantaviruses. We analyzed the permissiveness of primary endothelial cells of the human pulmonary microvasculature and of primary human epithelial cells derived from bronchi, bronchioles and alveoli for Old World orthohantavirus Puumala virus (PUUV) in vitro. In addition, we examined the expression of orthohantaviral receptors in these cell types. To minimize donor-specific effects, cells from two different donors were tested for each cell type. Productive infection with PUUV was observed for endothelial cells of the microvasculature and for the three tested epithelial cell types derived from different sites of the respiratory tract. Interestingly, infection and particle release were also detected in bronchial and bronchiolar epithelial cells although expression of the orthohantaviral receptor integrin β3 was not detectable in these cell types. In addition, replication kinetics and viral release demonstrate enormous donor-specific variations. The human respiratory epithelium is among the first targets of orthohantaviral infection and may contribute to virus replication, dissemination and pathogenesis of HFRS-causing orthohantaviruses. Differences in initial pulmonary infection due to donor-specific factors may play a role in the observed broad variance of severity and symptoms of orthohantavirus disease in patients. The absence of detectable levels of integrin αVβ3 surface expression on bronchial and small airway epithelial cells indicates an alternate mode of orthohantaviral entry in these cells that is independent from integrin β3.

中文翻译：

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人类呼吸道细胞支持致病性旧大陆正汉坦病毒 Puumala 的复制

所有已知的致病性正汉坦病毒（汉坦病毒科）的传播通常通过吸入被感染啮齿动物衍生的病毒颗粒污染的气溶胶发生，感染的器官表现以肺部和肾脏受累为特征。在欧亚大陆发现的正汉坦病毒引起肾综合征出血热 (HFRS)，新世界正汉坦病毒引起汉坦病毒心肺综合征 (HCPS)。然而，也观察到了具有严重肺部表现的旧大陆正汉坦病毒感染病例。因此，人类气道细胞可能代表正汉坦病毒感染的初始目标，也可能在欧亚正汉坦病毒感染的发病机制中发挥作用。我们在体外分析了人肺微血管系统的原代内皮细胞和源自支气管、细支气管和肺泡的原代人上皮细胞对旧世界正汉坦病毒普马拉病毒 (PUUV) 的允许性。此外，我们检测了这些细胞类型中正汉病毒受体的表达。为了最大限度地减少供体特异性影响，针对每种细胞类型测试了来自两个不同供体的细胞。对于微脉管系统的内皮细胞和来自呼吸道不同部位的三种测试上皮细胞类型，观察到 PUUV 的生产性感染。有趣的是，在支气管和细支气管上皮细胞中也检测到感染和颗粒释放，尽管在这些细胞类型中未检测到正汉病毒受体整合素 β3 的表达。此外，复制动力学和病毒释放表现出巨大的供体特异性变异。人类呼吸道上皮细胞是原汉坦病毒感染的首要目标之一，并且可能有助于导致 HFRS 的原汉坦病毒的病毒复制、传播和发病机制。由于供体特异性因素导致的初始肺部感染差异可能在观察到的患者正汉坦病毒病严重程度和症状的广泛差异中起作用。支气管和小气道上皮细胞上缺乏可检测水平的整合素 αVβ3 表面表达，表明这些细胞中正汉病毒进入的另一种模式，独立于整合素 β3。人类呼吸道上皮细胞是原汉坦病毒感染的首要目标之一，并且可能有助于导致 HFRS 的原汉坦病毒的病毒复制、传播和发病机制。由于供体特异性因素导致的初始肺部感染差异可能在观察到的患者正汉坦病毒病严重程度和症状的广泛差异中起作用。支气管和小气道上皮细胞上缺乏可检测水平的整合素 αVβ3 表面表达，表明这些细胞中正汉病毒进入的另一种模式，独立于整合素 β3。人类呼吸道上皮细胞是原汉坦病毒感染的首要目标之一，并且可能有助于导致 HFRS 的原汉坦病毒的病毒复制、传播和发病机制。由于供体特异性因素导致的初始肺部感染差异可能在观察到的患者正汉坦病毒病严重程度和症状的广泛差异中起作用。支气管和小气道上皮细胞上缺乏可检测水平的整合素 αVβ3 表面表达，表明这些细胞中正汉病毒进入的另一种模式，独立于整合素 β3。由于供体特异性因素导致的初始肺部感染差异可能在观察到的患者正汉坦病毒病严重程度和症状的广泛差异中起作用。支气管和小气道上皮细胞上缺乏可检测水平的整合素 αVβ3 表面表达，表明这些细胞中正汉病毒进入的另一种模式，独立于整合素 β3。由于供体特异性因素导致的初始肺部感染差异可能在观察到的患者正汉坦病毒病严重程度和症状的广泛差异中起作用。支气管和小气道上皮细胞上缺乏可检测水平的整合素 αVβ3 表面表达，表明这些细胞中正汉病毒进入的另一种模式，独立于整合素 β3。