{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:58:33Z","timestamp":1790873913034,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Microbiology","reference-count":78,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Interferon gamma (IFN-\u03b3) is a potent cytokine secreted following primary varicella-zoster virus (VZV) infection. Our previous studies demonstrated that pretreatment with IFN-\u03b3 completely inhibited VZV replication in lung fibroblast MRC-5 and retinal epithelial ARPE-19 but not in melanoma MeWo cells, suggesting that IFN-\u03b3-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-\u03b3-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\n                  <jats:italic>trans<\/jats:italic>\n                  -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-\u03b3-induced restriction factors that inhibit VZV replication and suggest that suppression of JAK-STAT signaling can promote VZV replication in differentiated keratinocytes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>Varicella-zoster virus (VZV) is a ubiquitous human pathogen that causes chickenpox and shingles, which are characterized by the formation of fluid-filled skin lesions. Our results showed that MX1 and IFITM1 inhibited VZV replication both in ARPE-19 and MeWo cells. Unexpectedly, high levels of endogenous MX1 were detected in human primary epidermal Keratinocytes. Cell-free VZV could not infect human primary epidermal keratinocytes. It has been shown that calcium regulates the differentiation of keratinocytes. Suppressing MX1 expression with a JAK inhibitor increased VZV replication in calcium chloride-treated keratinocytes. These results indicate that both the expression level of endogenous MX1 and the differentiation status of the keratinocytes influence VZV replication in keratinocytes. Understanding the mechanisms by which MX1 and IFITM1 play roles in VZV gene programming may be important in determining the tissue restriction of VZV.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.28.754940","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:40:14Z","timestamp":1790653214000},"source":"Crossref","is-referenced-by-count":0,"title":["Interferon gamma-induced MX1 and IFITM1 inhibit Varicella-Zoster Virus Replication"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-8120","authenticated-orcid":false,"given":"Seong K.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health-Shreveport, Shreveport, Louisiana 71130-3932"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1739-8858","authenticated-orcid":false,"given":"Akhalesh K.","family":"Shakya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health-Shreveport, Shreveport, Louisiana 71130-3932"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-1741","authenticated-orcid":false,"given":"Hongyan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health-Shreveport, Shreveport, Louisiana 71130-3932"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100108501151000_2026.09.28.754940v1.1","unstructured":"Arvin A , Gilden D . 2013. 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