Department of Cell & Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Infectious Diseases, Imperial College London, London, UK.
Nat Commun. 2024 Nov 2;15(1):9480. doi: 10.1038/s41467-024-53791-4.
SARS-CoV-2 initiates infection in the conducting airways, where mucociliary clearance inhibits pathogen penetration. However, it is unclear how mucociliary clearance impacts SARS-CoV-2 spread after infection is established. To investigate viral spread at this site, we perform live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 12 days. Using a fluorescent reporter virus and markers for cilia and mucus, we longitudinally monitor mucus motion, ciliary motion, and infection. Infected cell numbers peak at 4 days post infection, forming characteristic foci that tracked mucus movement. Inhibition of MCC using physical and genetic perturbations limits foci. Later in infection, mucociliary clearance deteriorates. Increased mucus secretion accompanies ciliary motion defects, but mucociliary clearance and vectorial infection spread resume after mucus removal, suggesting that mucus secretion may mediate MCC deterioration. Our work shows that while MCC can facilitate SARS-CoV-2 spread after initial infection, subsequent MCC decreases inhibit spread, revealing a complex interplay between SARS-CoV-2 and MCC.
SARS-CoV-2 首先在传导气道中引发感染，在那里黏液纤毛清除作用抑制病原体穿透。然而，目前尚不清楚在感染建立后，黏液纤毛清除作用如何影响 SARS-CoV-2 的传播。为了研究该部位的病毒传播，我们对感染 SARS-CoV-2 的分化原代人支气管上皮培养物进行了长达 12 天的实时成像。我们使用荧光报告病毒和纤毛和黏液标志物，纵向监测黏液运动、纤毛运动和感染。感染后 4 天，受感染细胞数量达到峰值，形成了跟踪黏液运动的特征性病灶。使用物理和遗传干扰抑制 MCC 会限制病灶的形成。在感染后期，黏液纤毛清除作用恶化。随着纤毛运动缺陷，黏液分泌增加，但在清除黏液后，黏液纤毛清除和载体感染传播恢复，表明黏液分泌可能介导 MCC 恶化。我们的工作表明，虽然 MCC 可以促进初始感染后的 SARS-CoV-2 传播，但随后的 MCC 减少会抑制传播，揭示了 SARS-CoV-2 和 MCC 之间的复杂相互作用。
