Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120, Heidelberg, Germany.
Virol J. 2021 Aug 17;18(1):169. doi: 10.1186/s12985-021-01636-7.
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 β 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 αβ surface expression on bronchial and small airway epithelial cells indicates an alternate mode of orthohantaviral entry in these cells that is independent from integrin β.
所有已知的致病性正粘病毒（正粘病毒科）通常通过吸入受感染啮齿动物来源的病毒颗粒污染的气溶胶传播，感染的器官表现特征为肺和肾受累。欧亚大陆发现的正粘病毒引起肾综合征出血热（HFRS），而新世界正粘病毒引起汉坦病毒心肺综合征（HCPS）。然而，也观察到具有严重肺部表现的旧世界正粘病毒感染病例。因此，人类气道细胞可能代表正粘病毒感染的初始靶标，并且也可能在欧亚大陆正粘病毒感染的发病机制中发挥作用。
我们分析了人肺微血管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粘病毒普马拉病毒（PUUV）的体外易感性。此外，我们检查了这些细胞类型中存在的正粘病毒受体。为了尽量减少供体特异性影响，对每种细胞类型的两种不同供体的细胞进行了测试。
在微血管内皮细胞和三种来自不同呼吸道部位的测试上皮细胞类型中观察到了与 PUUV 的有效感染。有趣的是，尽管在这些细胞类型中未检测到正粘病毒受体整合素β的表达，但也检测到了支气管和细支气管上皮细胞的感染和颗粒释放。此外，复制动力学和病毒释放表明存在巨大的供体特异性差异。
人呼吸道上皮细胞是正粘病毒感染的首批靶标之一，可能有助于病毒复制、传播和引起 HFRS 的正粘病毒的发病机制。由于供体特异性因素导致的初始肺部感染的差异可能在患者中观察到的正粘病毒疾病严重程度和症状的广泛变化中发挥作用。支气管和小气道上皮细胞表面未检测到可检测水平的整合素αβ表达表明，在这些细胞中存在与整合素β无关的正粘病毒进入的替代模式。
