Influenza viruses pose a significant burden on global human health. Influenza has a broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and burden in the airways is not fully understood. Using primary human airway cultures, which recapitulate the diverse epithelial cell landscape of the human airways, we investigated the impact of cell type composition on virus tropism and replication kinetics. Cultures were highly diverse across multiple donors and 30 independent differentiation conditions and supported a range of influenza replication. Although many cell types were susceptible to influenza, ciliated and secretory cells were predominantly infected. Despite the strong tropism preference for secretory and ciliated cells, which consistently make up 75% or more of infected cells, only ciliated cells were associated with increased virus production. Surprisingly, infected secretory cells were associated with overall reduced virus output. The disparate response and contribution to influenza virus production could be due to different pro- and antiviral interferon-stimulated gene signatures between ciliated and secretory populations, which were interrogated with single-cell RNA sequencing. These data highlight the heterogeneous outcomes of influenza virus infections in the complex cellular environment of the human airway and the disparate impacts of infected cell identity on multiround burst size, even among preferentially infected cell types.

中文翻译：

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纤毛细胞的趋向性是人类呼吸道中流感病毒爆发大小的主要驱动因素


流感病毒对全球人类健康造成重大负担。流感在气道中具有广泛的细胞趋向性，但不同上皮细胞类型的感染如何影响气道中的复制动力学和负担尚不完全清楚。使用原代人类气道培养物，概括了人类气道的多样化上皮细胞景观，我们研究了细胞类型组成对病毒趋向性和复制动力学的影响。多个供体和 30 种独立分化条件下的培养物具有高度多样性，并支持一系列流感复制。尽管许多细胞类型对流感敏感，但纤毛细胞和分泌细胞主要受到感染。尽管分泌细胞和纤毛细胞具有强烈的趋向性偏好（它们始终占感染细胞的 75% 或更多），但只有纤毛细胞与病毒产量增加相关。令人惊讶的是，受感染的分泌细胞与病毒产量的总体减少有关。对流感病毒产生的不同反应和贡献可能是由于纤毛群体和分泌群体之间受促病毒和抗病毒干扰素刺激的基因特征不同所致，这些基因特征通过单细胞RNA测序进行了研究。这些数据强调了人类呼吸道复杂细胞环境中流感病毒感染的异质性结果，以及受感染细胞身份对多轮爆发大小的不同影响，即使在优先受感染的细胞类型中也是如此。