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

TL;DR

This study uses patient-derived lung organoids to model severe COVID-19 caused by a TLR3 mutation, showing how genetic factors influence disease severity.

Contribution

A novel patient-specific lung organoid model is developed to study the impact of TLR3 mutations on SARS-CoV-2 infection and disease severity.

Findings

TLR3-mutated lung organoids showed reduced TLR3 and downstream gene expression.

Infection increased fibrinogen gene expression, linked to severe COVID-19.

TLR3 expression was still inducible despite the loss-of-function mutation.

Abstract

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.

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