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<p>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 <i>TLR3</i> 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 <i>TLR3</i> 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 (<i>FGA</i>, <i>FGG</i>), which are associated with severe COVID-19. Interestingly, <i>TLR3</i> 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.</p>

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Modelling severe COVID-19 in TLR3-mutated hiPSCs-derived lung organoids

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月26日

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  • Andrea Latini,
  • Paola Spitalieri,
  • Federica Centofanti,
  • Barbara Rizzacasa,
  • Donatella Amatore,
  • Giorgia Grilli,
  • Riccardo De Santis,
  • Lorenzo Vaccaro,
  • Vito Luigi Colona,
  • Giulio Puleri,
  • Anna Maria Nardone,
  • Michela Biancolella,
  • Elena Campione,
  • Loredana Sarmati,
  • Paola Rogliani,
  • Davide Cacchiarelli,
  • Antonio Novelli,
  • Federica Sangiuolo,
  • Florigio Lista,
  • Giuseppe Novelli

摘要

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.