Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States
Ayden Fonseca
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States
Sahar Taheri
Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, San Diego, United States
Stella-Rita Ibeawuchi
Department of Pathology, University of California San Diego, San Diego, United States
Nathan Beutler
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, United States
Gajanan Dattatray Katkar
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States
Amanraj Claire
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States
Pulmonary Critical Care Section, Veterans Affairs (VA) San Diego Healthcare System, La Jolla, United States; Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
Ann Tipps
Department of Pathology, University of California San Diego, San Diego, United States
Grace Lin
Department of Pathology, University of California San Diego, San Diego, United States
Patricia A Thistlethwaite
Division of Cardiothoracic Surgery, University of California San Diego, San Diego, United States
Ranajoy Chattopadhyay
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States; Cell Applications Inc., La Jolla, CA, United States
Thomas F Rogers
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, United States; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, United States; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, United States
Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, San Diego, United States; Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; HUMANOID CoRE, University of California San Diego, San Diego, United States; Department of Medicine, University of California, San Diego, La Jolla, CA, United States
HUMANOID CoRE, University of California San Diego, San Diego, United States; Department of Pathology, University of California San Diego, San Diego, United States
Background: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. Methods: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Results: Infected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Conclusions: Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. Funding: This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).
