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Microbes & Immunity RANTES/CCL5 and ezrin peptide RepG3 for long COVID

proinflammatory cytokine expression in vascular smooth can directly attack tumor cells, particularly in patients with
muscle cells (VSMCs), regulates vascular function, and melanoma and lung carcinoma. NK cells play critical roles
reduces blood pressure. 70 in reducing lung metastases in mouse models, and high
levels of NK cell infiltrates generally correlate with effective
4.11. RANTES/CCL5 amplifies NK-cell activity tumor regression. Activated NK cells kill the targeted cancer
RANTES/CCL5 activates resting NK cells bound to the cells with cytolytic granules, including perforin, granzyme,
endothelial extracellular matrix, inducing polarization, and granulysin. Despite the strong potential of NK cells to
intracellular adhesion molecule expression, and receptor lyse tumor cells, NK cells rarely infiltrate solid tumors.
redistribution. RANTES/CCL5 amplifies the effectiveness NK cell infiltration of tumors is driven by high levels
of NK-cell killing in cells infected with viruses, bacteria, of RANTES/CCL5 homing. There is a strong positive
fungi, parasites, and cancer cells. The chemoattractant correlation between the expression of RANTES/CCL5
cytokine IL-15 acts in conjunction with RANTES/CCL5 in and the infiltration of NK cells in human melanoma and
this process, and the concentration gradients of RANTES/ other solid tumors. RANTES/CCL5 expression has been
CCL5 and IL-15 function together to induce NK cell detected in ovarian, prostate, and pancreatic cancers.
migration. The recruitment, migration, and extravasation High serum concentrations of RANTES/CCL5 correlate
of NK cells from blood vessels into target tissues are the first with better survival of patients with melanoma, while low
steps in the cascade of events leading to NK-cell/Target- RANTES/CCL5 expression correlates with deficiency of
cell conjugate formation and NK cytotoxic response. The NK-cell activity and tumor outgrowth.
cytokine expression profile and perforin-dependent lytic-
killing mechanism of NK cells resemble that of CTL. LCMV infection induces a high level of RANTES/
CCL5 expression and secretion, NK cell infiltration, NK
On stimulation of NK cells, the chemokine receptors cell-mediated cytotoxicity, and anti-tumor activity. LCMV
CCR5 and CCR2 are redistributed to the front edge of viral infection stimulates high levels of RANTES/CCL5
an NK cell. Video microscopy studies of the formation of in Ma-Mel-86 melanoma cell lines, and RANTES/CCL5-
effector NK-cell/target-cell conjugates show that NK-cell dependent, anti-cancer NK-cell killing of melanoma cells
binding to target cells is mainly by attachment of the NK leads to immune-mediated melanoma regression. In vivo
leading edge to the target cell. The ezrin-tethered adhesion mouse models of human melanoma show LCMV infection
receptors ICAM-1 and ICAM-3 are redistributed to the and replication, resulting in RANTES/CCL5 secretion,
rear uropod, which recruits more NK cells to attack the activation and recruitment of NK cells, induction of NK
target cells. NK cells also respond to RANTES/CCL5 by cell invasion of tumors, and fast tumor regression. 72
synthesizing chemotactic factors, such as IL-8, MIP-1α, and
MIP-1β, which attract more NK cells and CTLs. In NK cells, 5. Transcription, translation, and secretion
RANTES/CCL5 stimulates Ca mobilization and cytolytic of RANTES/CCL5
2+
granule release, regulates adhesiveness, and promotes
cytotoxic activity. During the formation of NK-cell/target- The adaptive immunity amplifier RANTES/CCL5 is
cell conjugates, NK cells also produce more RANTES/CCL5. transcribed from the CCL5 gene into mRNA in the
nucleus, translated into a 91-amino acid precursor protein
NK cell polarization can be induced in 30 min in vitro in the endoplasmic reticulum, cleaved into 68-amino
with 1 – 10 ng/mL RANTES/CCL5, which is essential for acid RANTES/CCL5, which is, then, secreted into the
the formation of conjugates between NK cells and their extracellular medium through the Golgi apparatus. The
target cells. In contrast, inhibition of cell polarization and expression of RANTES/CCL5 occurs in epithelial cells,
adhesion receptor redistribution blocks the formation of fibroblasts, monocytes/macrophages, and T-cells, but the
NK-cell/target-cell conjugates and the cytotoxic activity regulation and kinetics of RANTES/CCL5 expression
of NK cells. ADP-ribosylation of the GTP-binding protein varies between cell types.
RhoA also blocks cell polarization and the induction of
cytotoxic activity of NK cells, indicating the key role of 5.1. Induction of RANTES/CCL5 expression by viral
multi-protein complexes of EBP50+RhoA+ezrin+ICAM-1 infection
in the process. 71 In epithelial cells, fibroblasts, monocytes, and macrophages,
virus infection induces mRNA transcription of the CCL5
4.12. Anti-cancer effect of RANTES/CCL5: Induction gene within a few hours, followed by protein translation.
of NK cells that target tumors
There is a complex pattern of cooperation between various
Tumor antigen-specific cytotoxic CD8 T-cells, activated transcription factors that bind to the promoter region
+
natural killer (NK) cells, and antibody-mediated cytotoxicity of the RANTES/CCL5 gene, and multiple transcription

Volume 1 Issue 1 (2024) 12 doi: 10.36922/mi.2474