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bioRxiv · 10.64898/2026.09.28.754940

Interferon gamma-induced MX1 and IFITM1 inhibit Varicella-Zoster Virus Replication

Kim, S.·Shakya, A. K.·Guo, H.
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Abstract

Interferon gamma (IFN-{gamma}) is a potent cytokine secreted following primary varicella-zoster virus (VZV) infection. Our previous studies demonstrated that pretreatment with IFN-{gamma} completely inhibited VZV replication in lung fibroblast MRC-5 and retinal epithelial ARPE-19 but not in melanoma MeWo cells, suggesting that IFN-{gamma}-stimulated protein(s) inhibit viral replication. Our microarray analysis revealed that 34 interferon-stimulated genes (ISGs) were upregulated by greater than 2.5-fold at 8 h post-treatment in both ARPE-19 and MRC-5 cells compared to those of MeWo cells. The depletion of CTSS, GBP4, MX1, IFIT1, IFITM1 and IRF1 by siRNA in IFN-{gamma}-treated cells significantly increased VZV yields. Ectopic overexpression of interferon-induced myxovirus resistance 1 (MX1) or transmembrane protein 1 (IFITM1) significantly reduced VZV yield both in ARPE-19 and MeWo cells. IFITM1 abrogated viral major immediate-early IE62 protein-mediated trans-activation. IFITM1 reduced the level of VZV immediate-early IE62 protein, but not the IE62 mRNA, suggesting that IFITM1 expression reduces the expression level of IE62 by post-transcriptional regulation. Cell-free VZV failed to infect human primary epidermal keratinocytes, in which the basal level of endogenous MX1 gene expression is very high. Pharmacologic inhibition of JAK signaling reduced MX1 expression and enhanced VZV replication in calcium chloride-induced differentiated keratinocytes. Collectively, these findings identify MX1 and IFITM1 as key IFN-{gamma}-induced restriction factors that inhibit VZV replication and suggest that suppression of JAK-STAT signaling can promote VZV replication in differentiated keratinocytes.

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Kim, S., Shakya, A. K., Guo, H.. 2026-09-28. Interferon gamma-induced MX1 and IFITM1 inhibit Varicella-Zoster Virus Replication. https://doi.org/10.64898/2026.09.28.754940

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