tetano
Editor, Senior Moderator
J Med Virol
. 2024 Apr;96(4):e29579.
doi: 10.1002/jmv.29579. The use of human iPSC-derived alveolar organoids to explore SARS-CoV-2 variant infections and host responses
Chaitanya Gandikota[SUP] 1 2 [/SUP], Kishore Vaddadi[SUP] 1 2 [/SUP], Pulavendran Sivasami[SUP] 1 2 [/SUP], Chaoqun Huang[SUP] 1 2 [/SUP], Yurong Liang[SUP] 1 2 [/SUP], Samuel Pushparaj[SUP] 1 2 [/SUP], Xufang Deng[SUP] 2 3 [/SUP], Rudragouda Channappanava[SUP] 2 4 [/SUP], Jordan P Metcalf[SUP] 2 5 [/SUP], Lin Liu[SUP] 1 2 [/SUP]
Affiliations
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) primarily targets the respiratory system. Physiologically relevant human lung models are indispensable to investigate virus-induced host response and disease pathogenesis. In this study, we generated human induced pluripotent stem cell (iPSC)-derived alveolar organoids (AOs) using an established protocol that recapitulates the sequential steps of in vivo lung development. AOs express alveolar epithelial type II cell protein markers including pro-surfactant protein C and ATP binding cassette subfamily A member 3. Compared to primary human alveolar type II cells, AOs expressed higher mRNA levels of SARS-CoV-2 entry factors, angiotensin-converting enzyme 2 (ACE2), asialoglycoprotein receptor 1 (ASGR1) and basigin (CD147). Considering the localization of ACE2 on the apical side in AOs, we used three AO models, apical-in, sheared and apical-out for SARS-CoV-2 infection. All three models of AOs were robustly infected with the SARS-CoV-2 irrespective of ACE2 accessibility. Antibody blocking experiment revealed that ASGR1 was the main receptor for SARS-CoV2 entry from the basolateral in apical-in AOs. AOs supported the replication of SARS-CoV-2 variants WA1, Alpha, Beta, Delta, and Zeta and Omicron to a variable degree with WA1 being the highest and Omicron being the least. Transcriptomic profiling of infected AOs revealed the induction of inflammatory and interferon-related pathways with NF-κB signaling being the predominant host response. In summary, iPSC-derived AOs can serve as excellent human lung models to investigate infection of SARS-CoV-2 variants and host responses from both apical and basolateral sides.
Keywords: SARS coronavirus; immune responses; innate immunity; pathogenesis; virus classification.
. 2024 Apr;96(4):e29579.
doi: 10.1002/jmv.29579. The use of human iPSC-derived alveolar organoids to explore SARS-CoV-2 variant infections and host responses
Chaitanya Gandikota[SUP] 1 2 [/SUP], Kishore Vaddadi[SUP] 1 2 [/SUP], Pulavendran Sivasami[SUP] 1 2 [/SUP], Chaoqun Huang[SUP] 1 2 [/SUP], Yurong Liang[SUP] 1 2 [/SUP], Samuel Pushparaj[SUP] 1 2 [/SUP], Xufang Deng[SUP] 2 3 [/SUP], Rudragouda Channappanava[SUP] 2 4 [/SUP], Jordan P Metcalf[SUP] 2 5 [/SUP], Lin Liu[SUP] 1 2 [/SUP]
Affiliations
- PMID: 38572923
- DOI: 10.1002/jmv.29579
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) primarily targets the respiratory system. Physiologically relevant human lung models are indispensable to investigate virus-induced host response and disease pathogenesis. In this study, we generated human induced pluripotent stem cell (iPSC)-derived alveolar organoids (AOs) using an established protocol that recapitulates the sequential steps of in vivo lung development. AOs express alveolar epithelial type II cell protein markers including pro-surfactant protein C and ATP binding cassette subfamily A member 3. Compared to primary human alveolar type II cells, AOs expressed higher mRNA levels of SARS-CoV-2 entry factors, angiotensin-converting enzyme 2 (ACE2), asialoglycoprotein receptor 1 (ASGR1) and basigin (CD147). Considering the localization of ACE2 on the apical side in AOs, we used three AO models, apical-in, sheared and apical-out for SARS-CoV-2 infection. All three models of AOs were robustly infected with the SARS-CoV-2 irrespective of ACE2 accessibility. Antibody blocking experiment revealed that ASGR1 was the main receptor for SARS-CoV2 entry from the basolateral in apical-in AOs. AOs supported the replication of SARS-CoV-2 variants WA1, Alpha, Beta, Delta, and Zeta and Omicron to a variable degree with WA1 being the highest and Omicron being the least. Transcriptomic profiling of infected AOs revealed the induction of inflammatory and interferon-related pathways with NF-κB signaling being the predominant host response. In summary, iPSC-derived AOs can serve as excellent human lung models to investigate infection of SARS-CoV-2 variants and host responses from both apical and basolateral sides.
Keywords: SARS coronavirus; immune responses; innate immunity; pathogenesis; virus classification.