| Autor: |
Morrison CB; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Edwards CE; Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Shaffer KM; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Araba KC; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Wykoff JA; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Williams DR; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Asakura T; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Dang H; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Morton LC; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Gilmore RC; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., O'Neal WK; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Boucher RC; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Baric RS; Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Ehre C; Marsico Lung Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.; Department of Pediatrics/Pediatric Pulmonology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. |
| Abstrakt: |
Muco-obstructive lung diseases are typically associated with high risks of COVID-19 severity; however, allergic asthma showed reduced susceptibility. To investigate viral spread, primary human airway epithelial (HAE) cell cultures were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and host–virus interactions were examined via electron microscopy, immunohistochemistry, RNA in situ hybridization, and gene expression analyses. In HAE cell cultures, angiotensin-converting enzyme 2 (ACE2) expression governed cell tropism and viral load and was up-regulated by infection. Electron microscopy identified intense viral egress from infected ciliated cells and severe cytopathogenesis, culminating in the shedding of ciliated cells packed with virions, providing a large viral reservoir for spread and transmission. Intracellular stores of MUC5AC, a major airway mucin involved in asthma, were rapidly depleted, likely to trap viruses. To mimic asthmatic airways, HAE cells were treated with interleukin-13 (IL-13), which reduced viral titers, viral messenger RNA, and cell shedding, and significantly diminished the number of infected cells. Although mucus hyperproduction played a shielding role, IL-13–treated cells maintained a degree of protection despite the removal of mucus. Using Gene Expression Omnibus databases, bulk RNA-sequencing analyses revealed that IL-13 up-regulated genes controlling glycoprotein synthesis, ion transport, and antiviral processes (albeit not the typical interferon-induced genes) and down-regulated genes involved in cilial function and ribosomal processing. More precisely, we showed that IL-13 reduced ACE2 expression, intracellular viral load, and cell-to-cell transmission while increasing the cilial keratan sulfate coating. In conclusion, intense viral and cell shedding caused by SARS-CoV-2 infection was attenuated by IL-13, which affected viral entry, replication, and spread. |
