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Proc Natl Acad Sci U S A
. 2024 Jul 23;121(30):e2408109121.
doi: 10.1073/pnas.2408109121. Epub 2024 Jul 19. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response
Sandra L Leibel 1 2 , Rachael N McVicar 2 3 , Rabi Murad 3 , Elizabeth M Kwong 1 2 3 , Alex E Clark 4 , Asuka Alvarado 2 3 , Bethany A Grimmig 2 3 , Ruslan Nuryyev 2 3 , Randee E Young 1 , Jamie C Lee 1 , Weiqi Peng 1 , Yanfang P Zhu 1 , Eric Griffis 5 , Cameron J Nowell 6 , Brian James 3 , Suzie Alarcon 7 , Atul Malhotra 8 , Linden J Gearing 9 10 , Paul J Hertzog 9 10 , Cheska M Galapate 11 , Koen M O Galenkamp 3 , Cosimo Commisso 11 , Davey M Smith 4 , Xin Sun 1 , Aaron F Carlin 4 , Richard L Sidman 12 , Ben A Croker # 1 , Evan Y Snyder # 2 3
Affiliations
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.
Keywords: COVID-19; inflammation; lung organoids; macropinocytosis; surfactant.
. 2024 Jul 23;121(30):e2408109121.
doi: 10.1073/pnas.2408109121. Epub 2024 Jul 19. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response
Sandra L Leibel 1 2 , Rachael N McVicar 2 3 , Rabi Murad 3 , Elizabeth M Kwong 1 2 3 , Alex E Clark 4 , Asuka Alvarado 2 3 , Bethany A Grimmig 2 3 , Ruslan Nuryyev 2 3 , Randee E Young 1 , Jamie C Lee 1 , Weiqi Peng 1 , Yanfang P Zhu 1 , Eric Griffis 5 , Cameron J Nowell 6 , Brian James 3 , Suzie Alarcon 7 , Atul Malhotra 8 , Linden J Gearing 9 10 , Paul J Hertzog 9 10 , Cheska M Galapate 11 , Koen M O Galenkamp 3 , Cosimo Commisso 11 , Davey M Smith 4 , Xin Sun 1 , Aaron F Carlin 4 , Richard L Sidman 12 , Ben A Croker # 1 , Evan Y Snyder # 2 3
Affiliations
- PMID: 39028694
- DOI: 10.1073/pnas.2408109121
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.
Keywords: COVID-19; inflammation; lung organoids; macropinocytosis; surfactant.