@article{3966,
  author = {Sandra L. Leibel and Rachael N. McVicar and Rabi Murad and Elizabeth M. Kwong and Alex E. Clark and Asuka Alvarado and Bethany A. Grimmig and Ruslan Nuryyev and Randee E. Young and Jamie C. Lee and Weiqi Peng and Yanfang P. Zhu and Eric Griffis and Cameron J. Nowell and Brian James and Suzie Alarcon and Atul Malhotra and Linden J. Gearing and Paul J. Hertzog and Cheska M. Galapate and Koen M. O. Galenkamp and Cosimo Commisso and Davey M. Smith and Xin Sun and Aaron F. Carlin and Richard L. Sidman and Ben A. Croker and Evan Y. Snyder},
  title = {A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response},
  abstract = {The prevalence of “long COVID” is just one of the conundrums highlighting how little we know about the lung’s response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical “backdoor” route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell–intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.},
  year = {2024},
  journal = {Proceedings of the National Academy of Sciences},
  volume = {121},
  pages = {e2408109121},
  month = {2024-07-23},
  url = {https://www.pnas.org/doi/10.1073/pnas.2408109121},
  doi = {10.1073/pnas.2408109121},
}