The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense

Leibel, S. L.; McVicar, R. N.; Murad, R.; Kwong, E. M.; Clark, A. E.; Alvarado, A.; Grimmig, B. A.; Nuryyev, R.; Young, R. E.; Lee, J. C.; Peng, W.; Zhu, Y. P.; Griffis, E.; Nowell, C. J.; James, B.; Alarcon, S.; Malhotra, A.; Gearing, L. J.; Hertzog, P. J.; Galapate, C. M.; Galenkamp, K. M. O.; Commisso, C.; Smith, D. M.; Sun, X.; Carlin, A. F.; Croker, B. A.; Snyder, E. Y.

doi:10.1101/2023.01.26.525578

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bioRxiv · 10.1101/2023.01.26.525578

The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense

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Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. Using a novel multi-cell type, human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.

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Leibel, S. L., McVicar, R. N., Murad, R., Kwong, E. M., Clark, A. E., Alvarado, A., Grimmig, B. A., Nuryyev, R., Young, R. E., Lee, J. C., Peng, W., Zhu, Y. P., Griffis, E., Nowell, C. J., James, B., Alarcon, S., Malhotra, A., Gearing, L. J., Hertzog, P. J., Galapate, C. M., Galenkamp, K. M. O., Commisso, C., Smith, D. M., Sun, X., Carlin, A. F., Croker, B. A., Snyder, E. Y.. 2023-01-27. The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense. https://doi.org/10.1101/2023.01.26.525578

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