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In lipopolysaccharide-stimulated cells, RTD-1 inhibition of proinflammatory cytokine secretion and gene expression is mediated through inhibition of the NF-\u03baB and MAP kinase signaling pathways. To gain insights into RTD-1 regulation of na\u00efve cells, we performed RNA sequencing (RNA-seq) to determine the effect of the peptide on global gene expression in human monocytes and THP-1 monocytes. In both cell types, analysis of differentially expressed genes revealed stimulation of interferon and antiviral gene expression pathways. RTD-1 induced Y701 phosphorylation of STAT1 and activated the ISRE reporter in a JAK-dependent manner. Stimulation of the ISRE reporter by RTD-1 was interferon-\u03b1\/\u03b2 receptor dependent but was independent of its NF-\u03baB inhibitory activity in lipopolysaccharide-stimulated cells. RTD-1 inhibited infection of vesicular stomatitis virus pseudotyped with G glycoprotein or SARS-CoV-2 spike protein in THP-1 and Vero E6 cells, respectively. RTD-1 also inhibited infection of Calu-3 2B4 cells by SARS-CoV-2 virus, demonstrating antiviral activity of RTD-1 in diverse cell types. These results demonstrate that RTD-1 stimulates interferon and antiviral pathways, potentially priming cells for resistance to viral infection.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf150","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T12:04:23Z","timestamp":1761307463000},"source":"Crossref","is-referenced-by-count":1,"title":["The macrocyclic peptide rhesus theta defensin 1 activates interferon and antiviral pathways in human monocytes"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2112-6919","authenticated-orcid":false,"given":"Prasad","family":"Tongaonkar","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California , Los Angeles, CA 90033 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie K","family":"Trinh","sequence":"additional","affiliation":[{"name":"Department 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