The therapeutic potential of RANTES/CCL5 across diverse infections and its synergistic enhancement by ezrin peptide RepG3 for long COVID

Abstract

The amplification of anti-infective immunity against a wide spectrum of acute and chronic infections caused by various pathogens is mediated by RANTES/CCL5. This chemokine controls infections caused by viruses, bacteria, fungi, and protozoans. In addition, RANTES/CCL5 exhibits anti-cancer effects by increasing NK-cell activity and targeting tumors. RANTES/CCL5 acts by amplifying antigen-specific immunity on mucosal surfaces, programmed T-cell responses, cytotoxic T lymphocytes (CTL), B-cell activation, and antibody production. RANTES/CCL5 exerts its effects by binding to C-C receptors, thereby triggering JAK/STAT signaling and inducing the migration of lymphocytes, NK cells, and monocytes. In the brain, RANTES/CCL5 activates astrocytes and upregulates anti-inflammatory interleukin (IL)-10 expression. Inflammatory cytokines rapidly induce RANTES/CCL5 expression in fibroblasts, epithelial cells, and monocytes/macrophages. In T-cells, RANTES/CCL5 expression is mediated by translational control of the transcription factor RFLAT-1/KLF13, which is responsible for a 3-day delay in RANTES/CCL5 secretion after T-cell activation. A cell membrane multi-protein complex containing CFTR, EBP50, ezrin, and PKC is a dominant regulator of both RANTES/CCL5 and inflammatory cytokine expression. Treatment of a volunteer patient suffering from long COVID/vaccine injury with the ezrin peptide RepG3 alleviated symptoms, substantially reduced serum proinflammatory cytokines to normal levels, and enhanced the expression of RANTES/CCL5. The immune amplification activities of RANTES/CCL5 and the ezrin peptide RepG3 exhibit striking similarities. In contrast, the ezrin peptide RepG3 differs from RANTES/CCL5 in its ability to significantly inhibit the expression of proinflammatory cytokines IL-1β, IL-6, IL-8, IL-13, TNF-α, and proinflammatory chemokines MIP-1α and MIP-1β. The mechanism through which the ezrin peptide RepG3 enhances adaptive immunity likely involves its induction of systemic elevation of RANTES/CCL5 expression and the simultaneous inhibition of proinflammatory cytokine expression.