TY - JOUR
AU - Sandra L. Leibel
AU - Rachael N. McVicar
AU - Rabi Murad
AU - Elizabeth M. Kwong
AU - Alex E. Clark
AU - Asuka Alvarado
AU - Bethany A. Grimmig
AU - Ruslan Nuryyev
AU - Randee E. Young
AU - Jamie C. Lee
AU - Weiqi Peng
AU - Yanfang P. Zhu
AU - Eric Griffis
AU - Cameron J. Nowell
AU - Brian James
AU - Suzie Alarcon
AU - Atul Malhotra
AU - Linden J. Gearing
AU - Paul J. Hertzog
AU - Cheska M. Galapate
AU - Koen M. O. Galenkamp
AU - Cosimo Commisso
AU - Davey M. Smith
AU - Xin Sun
AU - Aaron F. Carlin
AU - Richard L. Sidman
AU - Ben A. Croker
AU - Evan Y. Snyder
AB - 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.
BT - Proceedings of the National Academy of Sciences
DA - 2024-07-23
DO - 10.1073/pnas.2408109121
IS - 30
N2 - 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.
PY - 2024
EP - e2408109121
T2 - Proceedings of the National Academy of Sciences
TI - A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response
UR - https://www.pnas.org/doi/10.1073/pnas.2408109121
VL - 121
Y2 - 2024-08-13
ER -