Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.
Dong YangJasper Fuk-Woo ChanChaemin YoonTsz-Yat LukHuiping ShuaiYuxin HouXiner HuangBingjie HuYue ChaiTerrence Tsz-Tai YuenYuanchen LiuTianrenzheng ZhuHuan LiuJialu ShiYang WangYixin HeKo-Yung SitWing-Kuk AuAnna Jinxia ZhangShuo-Feng YuanBao-Zhong ZhangYao-Wei HuangHin ChuPublished in: Journal of medical virology (2024)
Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNβ treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.
Keyphrases
- sars cov
- dendritic cells
- immune response
- respiratory syndrome coronavirus
- induced apoptosis
- inflammatory response
- gene expression
- cell cycle arrest
- cell death
- signaling pathway
- dna methylation
- endoplasmic reticulum stress
- lipopolysaccharide induced
- long non coding rna
- lps induced
- smoking cessation
- replacement therapy