Abstract
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.
Keywords: IL-13 cytokine; SARS-CoV-2; asthma; human airway epithelial cells; infection.
【저자키워드】 SARS-CoV-2, Asthma, IL-13 cytokine, human airway epithelial cells, infection., 【초록키워드】 COVID-19, viruses, Asthma, immunohistochemistry, ACE2, coronavirus, Antiviral, SARS-COV-2 infection, susceptibility, Infection, COVID-19 severity, interferon, Lung disease, Transmission, severe acute respiratory syndrome Coronavirus, viral spread, angiotensin-converting enzyme 2, viral entry, airway, RNA, Replication, Spread, electron microscopy, interleukin, Viral load, cells, Microscopy, Cell culture, shedding, epithelial cells, cell tropism, glycoprotein, mucin, ACE2 expression, expression, epithelial, RNA-sequencing, In situ hybridization, Angiotensin-converting enzyme, IL-13, Mucus, angiotensin, human airway epithelial cells, Viral reservoir, Allergic asthma, airways, high risk, ciliated cells, sulfate, Transport, shielding, HAE, Messenger RNA, interleukin-13, acute respiratory syndrome, ciliated cell, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, enzyme, infected cells, removal, asthmatic, human airway, Gene Expression Omnibus, viral titers, virions, cell cultures, TRAP, Intracellular, MUC5AC, down-regulated genes, primary human airway, Genes, Cell, gene expression analyses, keratan sulfate, affected, were infected, examined, caused, significantly, involved, reduced, treated, analysis, human airway epithelial, up-regulated, host–virus interaction, number of infected, down-regulated gene, viral egress, 【제목키워드】 airway, mechanism, Cell, affected, cause,