Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids

Xiaojuan Liu, Cun Li, Zhixin Wan, Man Chun Chiu, Jingjing Huang, Yifei Yu, Lin Zhu, Jian Piao Cai, Lei Rong, You Qiang Song, Hin Chu, Zongwei Cai, Shibo Jiang*, Kwok Yung Yuen*, Jie Zhou*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

2 Citations (Scopus)

Abstract

Horseshoe bats host numerous SARS-related coronaviruses without overt disease signs. Bat intestinal organoids, a unique model of bat intestinal epithelium, allow direct comparison with human intestinal organoids. We sought to unravel the cellular mechanism(s) underlying bat tolerance of coronaviruses by comparing the innate immunity in bat and human organoids. We optimized the culture medium, which enabled a consecutive passage of bat intestinal organoids for over one year. Basal expression levels of IFNs and IFN-stimulated genes were higher in bat organoids than in their human counterparts. Notably, bat organoids mounted a more rapid, robust and prolonged antiviral defense than human organoids upon Poly(I:C) stimulation. TLR3 and RLR might be the conserved pathways mediating antiviral response in bat and human intestinal organoids. The susceptibility of bat organoids to a bat coronavirus CoV-HKU4, but resistance to EV-71, an enterovirus of exclusive human origin, indicated that bat organoids adequately recapitulated the authentic susceptibility of bats to certain viruses. Importantly, TLR3/RLR inhibition in bat organoids significantly boosted viral growth in the early phase after SARS-CoV-2 or CoV-HKU4 infection. Collectively, the higher basal expression of antiviral genes, especially more rapid and robust induction of innate immune response, empowered bat cells to curtail virus propagation in the early phase of infection.

Original languageEnglish
Article number392
Number of pages12
JournalSignal Transduction and Targeted Therapy
Volume7
DOIs
Publication statusPublished - 19 Dec 2022

Scopus Subject Areas

  • Genetics
  • Cancer Research

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