TY - JOUR
T1 - Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids
AU - Liu, Xiaojuan
AU - Li, Cun
AU - Wan, Zhixin
AU - Chiu, Man Chun
AU - Huang, Jingjing
AU - Yu, Yifei
AU - Zhu, Lin
AU - Cai, Jian Piao
AU - Rong, Lei
AU - Song, You Qiang
AU - Chu, Hin
AU - Cai, Zongwei
AU - Jiang, Shibo
AU - Yuen, Kwok Yung
AU - Zhou, Jie
N1 - Funding Information:
We thank Professors Christopher Garcia (Standford University) and Hans Clevers (Hubrecht Institute) for sharing the Wnt surrogate plasmid. We thank the Center of PanorOmic Sciences and Electron Microscope Unit, Li Ka Shing Faculty of Medicine, University of Hong Kong, for assistance in confocal imaging flow cytometry, and electron microscopy. This work was partly supported by funding from the Health and Medical Research Fund (HMRF, 17161272 and 19180392) of the Food and Health Bureau of the HKSAR government to J.Z.; General Research Fund (GRF, 17105420), Collaborative Research Fund (CRF, C7042-21G) and Theme-based Research Scheme (TbRS, T11-709/21-N) of the Research Grants Council of HKSAR government to J.Z.; Health@InnoHK, Innovation and Technology Commission, HKSAR Government to K.Y.Y.
Publisher Copyright:
© The Author(s) 2022
PY - 2022/12/19
Y1 - 2022/12/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144329051&partnerID=8YFLogxK
U2 - 10.1038/s41392-022-01247-w
DO - 10.1038/s41392-022-01247-w
M3 - Journal article
C2 - 36529763
SN - 2095-9907
VL - 7
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
M1 - 392
ER -