{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Leibel SL"],"funding":["NIAID NIH HHS","HHS | NIH | National Cancer Institute","NHLBI NIH HHS","NCI NIH HHS","HHS | NIH | National Institute of Allergy and Infectious Diseases","California Institute for Regenerative Medicine","California Institute for Regenerative Medicine (CIRM)","HHS | NIH | National Cancer Institute (NCI)","NIH HHS","HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)"],"pagination":["e2408109121"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11287264"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["121(30)"],"pubmed_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."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response."],"pmcid":["PMC11287264"],"funding_grant_id":["R01 HL157985","3R01CA207189-05S1","S10 OD026929","P30 AI036214","AI036214","DISC2COVID19-12022","T32 HL166127","R01 CA207189"],"pubmed_authors":["Lee JC","Griffis E","Peng W","James B","Nowell CJ","Kwong EM","Alvarado A","Gearing LJ","McVicar RN","Carlin AF","Leibel SL","Grimmig BA","Commisso C","Galapate CM","Young RE","Croker BA","Hertzog PJ","Murad R","Malhotra A","Sidman RL","Snyder EY","Sun X","Smith DM","Nuryyev R","Alarcon S","Zhu YP","Galenkamp KMO","Clark AE"],"additional_accession":[]},"is_claimable":false,"name":"A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-07-02T03:22:44.245Z","creation":"2026-07-02T03:12:35.036Z"},"accession":"S-EPMC11287264","cross_references":{"pubmed":["39028694"],"doi":["10.1073/pnas.2408109121"]}}