J Leukoc Biol. 2025 Oct 25:qiaf150. doi: 10.1093/jleuko/qiaf150. Online ahead of print.
ABSTRACT
Rhesus theta defensin (RTD)-1, a cyclic antimicrobial peptide, regulates gene expression and immune signaling pathways in cell culture and animal models of immune mediated diseases. In LPS stimulated cells, RTD-1 inhibition of pro-inflammatory cytokine secretion and gene expression is mediated through inhibition of the NF-κB and MAP kinase signaling pathways. To gain insights into RTD-1 regulation of naïve 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 Interferon Stimulated Response Element (ISRE) reporter in a Janus Kinase (JAK) dependent manner. Stimulation of the ISRE reporter by RTD-1 was Interferon-alpha/beta receptor dependent but was independent of its NF-κB inhibitory activity in LPS stimulated cells. RTD-1 inhibited infection of vesicular stomatitis virus (VSV) pseudotyped with G glycoprotein or Severe Acute Respiratory Syndrome Coronavirus 2 (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.
PMID:41139211 | DOI:10.1093/jleuko/qiaf150