Page 10 - MI-1-1

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

interfere with effective immunity to acute infections. A poor
RANTES response results in failure to prevent virus infection
from spreading from the site of initial infection to other
tissues and failure to prevent the development of a chronic
systemic infection, resulting in more severe disease. 20

Expression of RANTES/CCL5 is important in mucosal
defense in response to viral and parasitic infection. In
21
general, RANTES/CCL5 amplifies programmed antigen-
specific mucosal immune responses by activating the
proliferation of antigen-specific T-lymphocytes. RANTES/
CCL5 is also a potent chemoattractant for CD8 cytotoxic
+
T-cells, monocytes/macrophages, eosinophils, basophils,
natural killer (NK) cells, and memory T lymphocytes.
RANTES/CCL5 mediates degranulation of basophils
and induces degranulation of eosinophils. In addition,
administration of RANTES/CCL5 in vitro in cell culture
induces transendothelial migration of monocytes/
macrophages, NK cells, and T-cells. 22
In mice, gene-knock-out experiments revealed the
importance of RANTES/CCL5 in infection defense.
Null-RANTES/CCL5 mutants have poor virus-specific
CD8 T-cell responses, express higher levels of inhibitory
+
receptors consistent with severe T-cell exhaustion, and
Figure 2. Efficacy of ezrin peptide RepG3 in enhancing RANTES/ have only very low levels of cytokine production. This
CCL5 expression. Effect of ezrin peptide RepG3 (2 mg/day) on elevated defect in immunity resembles the poor CD8 T-cell
+
RANTES/CCL5 chemokine expression in a long COVID/vaccine injury responses in the absence of CD4 T-cell help, similar to the
+
patient before and after 10 days of spray-inhalation therapy.
poor CD8 T-cell function in CD4 T-cell-depleted mice.
+
+
CD4 T-cell help induced by RANTES/CCL5 is vital in a
+
of memory T-cell clones. RANTES was identified as a number of chronic viral infections such as lymphocytic
68-amino acid, 7809 Da molecular-weight polypeptide. choriomeningitis virus (LCMV), hepatitis C virus (HCV),
RANTES is also referred to as CCL5: “Chemokine C-C and human immunodeficiency virus (HIV). 23
ligand 5;” therefore, to avoid confusion hereinafter, it shall
be referred to as RANTES/CCL5 (Figure 3). RANTES/CCL5 is involved in all stages of T-cell
19
maturation and response, from recruitment of naive
Further, research revealed that the chemokine RANTES/ T-cells within lymphoid organs, which become activated
CCL5 is expressed and secreted by a range of cell types, in the lymph nodes and spleen, to programmed antigen-
including epithelial cells, T-cells, NK cells, fibroblasts, and specific cytotoxic effector cells acting at sites of infection.
platelets. RANTES/CCL5 enhances the development of RANTES/CCL5 is also important for establishing reserves
mucosal and systemic immunity by amplifying cytokine of memory T-cells that can rapidly respond to repeated
secretion, antibody formation, and costimulatory receptor infection. RANTES/CCL5 is also essential for lymphocyte
24
expression and is a potent chemokine that attracts T-cells migration, such as the movement of activated T-cells from
and NK cells to sites of infection and inflammation, where lymphoid tissues to sites of infection.
it supports cytotoxic T lymphocytes (CTL) responses and
NK killing of target cells. 3.1. RANTES/CCL5 and viral infection
RANTES/CCL5 is produced by the expression of the The production of RANTES/CCL5 occurs during viral
CCL5 gene on human chromosome 17, normally under the infections of the respiratory tract. These include infections
control of the transcription factor “cAMP response element- caused by coronaviruses, influenza viruses, hantavirus,
binding protein” (CREB) and related transcription factor reovirus, adenovirus, coxsackie virus, rhinovirus, and
AP-1. However, under inflammatory conditions, RANTES/ respiratory syncytial virus (RSV). 25,26 In the absence of
CCL5 is additionally expressed by the Rel family of RANTES/CCL5 signaling, viral load after infection is
transcription factors, including NF-κB (p65/p50). Defects in higher and more likely to become chronic. Severe acute
RANTES/CCL5 expression or defects in its CCR5 receptor respiratory syndrome coronavirus-2 (SARS-CoV-2), HIV,

Volume 1 Issue 1 (2024) 4 doi: 10.36922/mi.2474