The use of human iPSC-derived alveolar organoids to explore SARS-CoV-2 variant infections and host responses

  • J Med Virol. 2024 Apr;96(4):e29579. doi: 10.1002/jmv.29579.
Chaitanya Gandikota  1  2 ,  Kishore Vaddadi  1  2 ,  Pulavendran Sivasami  1  2 ,  Chaoqun Huang  1  2 ,  Yurong Liang  1  2 ,  Samuel Pushparaj  1  2 ,  Xufang Deng  2  3 ,  Rudragouda Channappanava  2  4 ,  Jordan P Metcalf  2  5 ,  Lin Liu  1  2
Affiliations
  • 1. Department of Physiological Sciences, The Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Oklahoma State University, Stillwater, Oklahoma, USA.
  • 2. Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.
  • 3. Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA.
  • 4. Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, Oklahoma, USA.
  • 5. Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
PMID: 38572923 DOI: 10.1002/jmv.29579
Abstract

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.
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