Breugem Tim I, Riesebosch Samra, Zhang Jingshu, Mykytyn Anna Z, Krabbendam Lisette, Groen Nathalie, Baptista Varela Sivana, Schipper Debby, van den Doel Petra B, van Acker Romy, Stadhouders Ralph, Lamers Mart M, Haagmans Bart L
Viroscience Department, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands.
Pulmonary Medicine Department, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2410630122. doi: 10.1073/pnas.2410630122. Epub 2025 Mar 6.
Transmissibility of respiratory viruses is a complex viral trait that is intricately linked to tropism. Several highly transmissible viruses, including severe acute respiratory syndrome coronavirus 2 and Influenza viruses, specifically target multiciliated cells in the upper respiratory tract to facilitate efficient human-to-human transmission. In contrast, the zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) generally transmits poorly between humans, which is largely attributed to the absence of its receptor dipeptidyl peptidase 4 (DPP4) in the upper respiratory tract. At the same time, MERS-CoV epidemiology is characterized by occasional superspreading events, suggesting that some individuals can disseminate this virus effectively. Here, we utilized well-differentiated human pulmonary and nasal airway organoid-derived cultures to further delineate the respiratory tropism of MERS-CoV. We find that MERS-CoV replicated to high titers in both pulmonary and nasal airway cultures. Using single-cell messenger-RNA sequencing, immunofluorescence, and immunohistochemistry, we show that MERS-CoV preferentially targeted multiciliated cells, leading to loss of ciliary coverage. MERS-CoV cellular tropism was dependent on the differentiation of the organoid-derived cultures, and replication efficiency varied considerably between donors. Similarly, variable and focal expression of DPP4 was revealed in human nose tissues. This study indicates that the upper respiratory tract tropism of MERS-CoV may vary between individuals due to differences in DPP4 expression, providing an explanation for the unpredictable transmission pattern of MERS-CoV.
呼吸道病毒的传播性是一种复杂的病毒特性，与嗜性密切相关。几种高度可传播的病毒，包括严重急性呼吸综合征冠状病毒2和流感病毒，特别靶向于上呼吸道中的多纤毛细胞，以促进有效的人际传播。相比之下，人畜共患的中东呼吸综合征冠状病毒（MERS-CoV）在人与人之间的传播通常较差，这在很大程度上归因于其上呼吸道中缺乏其受体二肽基肽酶4（DPP4）。同时，MERS-CoV流行病学的特征是偶尔出现超级传播事件，这表明一些个体可以有效地传播这种病毒。在这里，我们利用分化良好的人肺和鼻气道类器官衍生培养物来进一步描绘MERS-CoV的呼吸道嗜性。我们发现MERS-CoV在肺和鼻气道培养物中均复制到高滴度。使用单细胞信使核糖核酸测序、免疫荧光和免疫组织化学，我们表明MERS-CoV优先靶向多纤毛细胞，导致纤毛覆盖丧失。MERS-CoV的细胞嗜性取决于类器官衍生培养物的分化，并且不同供体之间的复制效率差异很大。同样，在人鼻组织中发现了DPP4的可变和局灶性表达。这项研究表明，由于DPP4表达的差异，MERS-CoV在上呼吸道的嗜性可能因人而异，这为MERS-CoV不可预测的传播模式提供了解释。
