tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Rachael N McVicar[SUP] 2 3 [/SUP], Rabi Murad[SUP] 3 [/SUP], Elizabeth M Kwong[SUP] 1 2 3 [/SUP], Alex E Clark[SUP] 4 [/SUP], Asuka Alvarado[SUP] 2 3 [/SUP], Bethany A Grimmig[SUP] 2 3 [/SUP], Ruslan Nuryyev[SUP] 2 3 [/SUP], Randee E Young[SUP] 1 [/SUP], Jamie C Lee[SUP] 1 [/SUP], Weiqi Peng[SUP] 1 [/SUP], Yanfang P Zhu[SUP] 1 [/SUP], Eric Griffis[SUP] 5 [/SUP], Cameron J Nowell[SUP] 6 [/SUP], Brian James[SUP] 3 [/SUP], Suzie Alarcon[SUP] 7 [/SUP], Atul Malhotra[SUP] 8 [/SUP], Linden J Gearing[SUP] 9 10 [/SUP], Paul J Hertzog[SUP] 9 10 [/SUP], Cheska M Galapate[SUP] 11 [/SUP], Koen M O Galenkamp[SUP] 3 [/SUP], Cosimo Commisso[SUP] 11 [/SUP], Davey M Smith[SUP] 4 [/SUP], Xin Sun[SUP] 1 [/SUP], Aaron F Carlin[SUP] 4 [/SUP], Richard L Sidman[SUP] 12 [/SUP], Ben A Croker[SUP] #[/SUP][SUP] 1 [/SUP], Evan Y Snyder[SUP] #[/SUP][SUP] 2 3 [/SUP]
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[SUP] 1 2 [/SUP], Rachael N McVicar[SUP] 2 3 [/SUP], Rabi Murad[SUP] 3 [/SUP], Elizabeth M Kwong[SUP] 1 2 3 [/SUP], Alex E Clark[SUP] 4 [/SUP], Asuka Alvarado[SUP] 2 3 [/SUP], Bethany A Grimmig[SUP] 2 3 [/SUP], Ruslan Nuryyev[SUP] 2 3 [/SUP], Randee E Young[SUP] 1 [/SUP], Jamie C Lee[SUP] 1 [/SUP], Weiqi Peng[SUP] 1 [/SUP], Yanfang P Zhu[SUP] 1 [/SUP], Eric Griffis[SUP] 5 [/SUP], Cameron J Nowell[SUP] 6 [/SUP], Brian James[SUP] 3 [/SUP], Suzie Alarcon[SUP] 7 [/SUP], Atul Malhotra[SUP] 8 [/SUP], Linden J Gearing[SUP] 9 10 [/SUP], Paul J Hertzog[SUP] 9 10 [/SUP], Cheska M Galapate[SUP] 11 [/SUP], Koen M O Galenkamp[SUP] 3 [/SUP], Cosimo Commisso[SUP] 11 [/SUP], Davey M Smith[SUP] 4 [/SUP], Xin Sun[SUP] 1 [/SUP], Aaron F Carlin[SUP] 4 [/SUP], Richard L Sidman[SUP] 12 [/SUP], Ben A Croker[SUP] #[/SUP][SUP] 1 [/SUP], Evan Y Snyder[SUP] #[/SUP][SUP] 2 3 [/SUP]
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.