Modelling severe COVID-19 in TLR3-mutated hiPSCs-derived lung organoids
Clinical variability in COVID-19 is partly explained by host genetic factors, including inborn errors of immunity. We investigated a patient with a heterozygous nonsense mutation in the TLR3 gene (p.Trp769*) by generating human-induced pluripotent stem cells (hiPSCs) and differentiating them into lung organoids (hLORGs). TLR3-mutated hLORGs showed reduced basal expression of TLR3 and downstream signaling genes. Following infection with a pseudotyped SARS-CoV-2 virus and live SARS-CoV-2, RNA-Seq and qPCR analyses revealed significant upregulation of fibrinogen genes (FGA, FGG), which are associated with severe COVID-19. Interestingly, TLR3 expression remained inducible upon infection, despite the loss-of-function mutation. Our patient-derived hLORG model recapitulates the pathophysiological features of the patient and provides a platform to investigate host-virus interactions and test targeted therapies for genetically at-risk individuals.
Authors
- Anna Maria Nardone
- Antonio Novelli (ORCID: https://orcid.org/0000-0002-2889-6967)
- Federica Centofanti (ORCID: https://orcid.org/0000-0001-5731-2812)
- Davide Cacchiarelli (ORCID: https://orcid.org/0000-0002-9621-6716)
- Vito Luigi Colona (ORCID: https://orcid.org/0000-0002-9660-7397)
- Michela Biancolella (ORCID: https://orcid.org/0000-0002-9376-4231)
- Paola Paola Rogliani
- L. Sarmati
- Giulio Puleri
- Donatella Amatore (ORCID: https://orcid.org/0000-0001-5701-9683)
- Andrea Latini (ORCID: https://orcid.org/0000-0002-5350-7361)
- Barbara Rizzacasa (ORCID: https://orcid.org/0000-0002-4820-4403)
- Elena Campione (ORCID: https://orcid.org/0000-0001-7447-6798)
- Lorenzo Vaccaro (ORCID: https://orcid.org/0000-0002-8233-3241)
- Giorgia Grilli (ORCID: https://orcid.org/0009-0009-4993-6823)
- P. Spitalieri
- G. Novelli
- Federica Sangiuolo
- Florigio Lista
- Riccardo De Santis
Institutions
- University of Rome Tor Vergata (IT)
- Saint Camillus International University of Health and Medical Sciences (IT)
- Catholic University Our Lady of Good Counsel (AL)
- Ministry of Defence (IT)
- Bambino Gesù Children's Hospital (IT)
- Policlinico Tor Vergata (IT)
- Scuola Superiore Meridionale (IT)
- Telethon Institute Of Genetics And Medicine (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Medical Research Foundation (GB)
- University of Naples Federico II (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-12-26
- DOI
- https://doi.org/10.1038/s41420-025-02936-5
- Primary Topic
- Respiratory viral infections research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Giovanni Armenise-Harvard Foundation
- European Commission
- Fondazione Telethon
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro