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

induces the phosphorylation and activation of Janus G-protein Gαi family also inhibits Adenylyl Cyclase
Kinases (JAKs) associated with the cytoplasmic tail of the (AC), reducing intracellular cAMP concentrations and
receptor. Activated JAKs phosphorylate and activate signal inhibiting the activity of PKA. This negative feedback loop
transducer and activator of transcriptions (STATs), which inhibits PKA activation of the transcription factor CREB
dimerize and migrate to the nucleus to transcribe their and prevents additional CCR5 transcription. However,
target genes. 50 CCR5 can still support CREB-mediated IL-10 expression
through ERK > RSK > CREB signaling and also through
Nanomolar concentrations of RANTES/CCL5 induce 58-60
activation of JAKs, rapid tyrosine phosphorylation, and STAT transcription.
activation of STAT1 and STAT3 in T-cells, followed The G-protein Gαq family activates phospho-
by binding to DNA in the nucleus within 30 min. The lipase-C (PLC), the conversion of phosphatidyl-inositol
result of JAK-STAT signaling is increased in intracellular 4,5-bisphosphate (PI (4,5) P2) to diacylglycerol (DAG)
calcium ion concentration, the expression of T-helper and inositol-1,4,5-trisphosphate (IP3), which elevates
differentiation proteins, upregulation of the IL-2 receptor, intracellular Ca . The combination of elevated Ca
2+
2+
production of cytokines, and T-cell proliferation. This and DAG activates PKC bound to ezrin in the signaling
amplification pathway for T-cells is independent of antigen complex. Activated PKC phosphorylates and activates p38
presentation but is important for the maintenance of MAPK, ERK1/2, and JNK, leading to cytokine expression,
memory T-cells. 51,52 leukocyte migration, chemotaxis, homing, and general
amplification of immune responses. 61,62 RANTES/CCL5
4.2. RANTES/CCL5 > CCR5 triggers multiple binding to CCR5 also induces Ras activation of the Ras >
G-protein cell-signaling pathways Raf > MEK > ERK pathway, leading to NF-κB activation
CCR5 forms multi-protein complexes with ezrin-binding and the expression of CD137, which has a major role in
63
phosphoprotein 50 (EBP50), ezrin, and G-protein immune regulation (Figure 4).
signaling systems. CCR5 predominantly couples to the 4.3. RANTES/CCL5 amplifies antigen-specific
G-alpha proteins Gαi/0 and Gαq/11 in T-cells, dendritic immunity on mucosal surfaces
cells, macrophages, eosinophils, and microglia. The
G-protein Gαi family activates phospho-inositol-3-kinases RANTES/CCL5 regulates and amplifies local antigen-
(PI3K) bound to ezrin, which converts phosphatidyl- specific immunity in the mucous membranes of the
inositol-2 (PIP2) to phosphatidyl-inositol-3 (PIP3) and airways, gut, and vagina. RANTES/CCL5 is produced by
stimulates Rho-GTPases, Rho-GEFs, Rac-GTPases, and airway epithelial cells, mucosal monocytes, macrophages,
the downstream activation of Pyruvate Dehydrogenase and T-cells in response to infectious agents, which
Kinase-1 (PDK1) and AKT (PKB). This results in increased then binds to different types of mucosal cells, attracts
cell adhesion, polarization, and survival. The activation lymphocytes to the focus of any infection, and is a potent
of PI3K also results in the rearrangement of the actin adjuvant for adaptive immune responses. The mucosal
polymer anchored to ezrin and the reorganization of the surfaces of epithelial cells also contain large numbers of
cytoskeleton. 53-55 lymphocytes embedded in the membrane, which secrete
RANTES/CCL5 and other chemokines. RANTES/CCL5
In antigen-presenting cells (APCs), such as dendritic induces Caco-2 gut epithelial mucosa cell lines to secrete
cells and macrophages, RANTES/CCL5 induces CCR5 chemokines that boost immune defense. RANTES/
signaling mediated by the G-protein Gαi family and the CCL5 also supports mucosal epithelial cells to transport
ezrin+PI3K > PDK1 > AKT (PKB) pathway to activate polymeric IgA into external secretions for local mucosal
the small transcription factor PU.1 to express CD80 (B7- antibody defense (Figure 5).
64
1) and CD86. These cell-surface costimulatory molecules
bind to the coreceptor CD28 on T-cells when APCs and 4.4. RANTES/CCL5 amplifies programmed T-cell and
T-cells interact. CD80, CD86, and MHC presenting B-cell adaptive immunity
peptide antigens on the surface of APCs bind to CD28, In healthy people, T-cells secrete RANTES/CCL5 into the
CD3, and the TCR on the surface of T-cells, resulting in extracellular medium, and normal physiological serum
IL-2 production, T-cell growth, cell division, proliferation, concentrations of RANTES/CCL5 are <1 nM, ranging from
and amplification of immune responses. 56,57
2 – 7 ng/mL. RANTES/CCL5 binds to CCR5 and amplifies
In contrast, regulatory T-cells constitutively express both primary and secondary programmed antigen-specific
CTLA4, which binds to CD80 or CD86 and induces immune responses of T-cells and B-cells. RANTES/CCL5
immunosuppressive functions that modulate T-cell induces CD4 T-cell help for B-cell responses, resulting
+
proliferation and play a role in immune tolerance. The in increased titers of antibodies and leading to a vigorous

Volume 1 Issue 1 (2024) 8 doi: 10.36922/mi.2474