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

1. Long COVID (post-acute sequelae of continued to express recombinant spike for more than
14
COVID [PASC]) and COVID-vaccine adverse 6 months. Vaccine-derived spike mRNA can be reverse
events transcribed into DNA, resulting in local genetic damage to
various human tissues and chronic systemic expression of
1.1. Spike protein and regulation of inflammation the spike. 15
Acute COVID is caused by the spike protein of SARS- 1.2. SARS-CoV-2 spike protein directly induces
CoV-2, binding to the ACE2 receptor on the surface of inflammation
target cells to initiate infection and also binding to toll-like
receptors (TLR2 and TLR4), triggering hyperinflammation. The pathogenesis of COVID is associated with
However, long after the SARS-CoV-2 viral load becomes hyperinflammatory responses. In human and mouse
undetectable and acute COVID symptoms subside, up macrophages and in mouse models, the spike (S) protein
to half of the patients can develop a chronic condition of SARS-CoV-2 induces inflammatory cytokines and
characterized by systemic inflammation, fatigue, “brain chemokines, including IL-1β, IL-4, IL-6, IL-8, TNF-
fog,” myocarditis, and other symptoms of long COVID/ α, CXCL1, CXCL2, CCL2, MIP-1α, and MIP-1β. No
post-acute sequelae of COVID. One explanation for such inflammatory response is observed in response to
1,2
the persistence of inflammation is that hyperexpression the membrane (M), envelope (E), and nucleocapsid(N)
of interleukin (IL)-1β, IL-6, and S100A8A9 during acute proteins of SARS-CoV-2. Biochemical studies revealed that
COVID triggers an unregulated self-stimulating TLR4- spike protein triggers inflammation through activation of
RAGE inflammatory loop, which maintains chronic the TLR4/TLR2 > MyD88 > mitogen-activated protein
3
systemic inflammation. However, evidence is accumulating kinase 38 (p38 MAPK) > NF-κB pathway. 16
that the expression of spike protein persists after SARS- The inducible nuclear transcription factor NF-κB
CoV-2 is no longer detected. Chronic expression of spike is essential for the expression of many genes involved
protein triggers inflammatory cytokines and chemokines, in inflammatory responses. In the cytoplasm, NF-κB
which could also explain the symptoms of long COVID/ is inactive because it is complexed with an inhibitor
PASC. 4,5 protein called IκB. Downstream activation signals
Two mRNA vaccines encoding spike protein antigen, from p38 MAPK result in the activation of IKK and the
BNT162b2 (ComirnatyTM) from Pfizer-BioNTech and the phosphorylation and degradation of IκB, which permits
mRNA-1273 of Moderna, received the United States Food the NF-κB components (p65, Rel-B, c-Rel, p50, and p52)
and Drug Administration emergency use authorization, to translocate into the nucleus and bind DNA as dimers
but a large number of serious adverse events have been at specific recognition elements in promoter regions of
reported following mRNA COVID vaccination. These NF-κB-responsive proinflammatory genes, resulting in the
serious adverse events may be related to the over 200,000 initiation of proinflammatory cytokine expression.
“excess deaths” reported in the United Kingdom, which have 1.3. Inhibition of p38 MAPK blocks SARS-CoV-2
emerged since the first use of mRNA vaccines in December inflammation
2020. In general, 90% of the population of England has
6-8
been vaccinated, but the monthly all-cause death rate in During SARS-CoV-2 viral entry and spike protein binding
the vaccinated population appears to be higher than that to TLR4/TLR2, the immunoregulatory kinase p38 MAPK
in the unvaccinated population and should be investigated is activated, driving harmful virus-induced inflammatory
further. It is now known that these vaccines can induce cytokine expression of IL-1β, IL-6, IL-8, TNF-α, IL12A,
9,10
the expression of spike protein in multiple tissues for more IL1A, IL7, and IL17A as well as inflammatory chemokines
than 6 months after the date of vaccination and cause CCL2, CCL3 plus M-CSF, GM-CSF, and G-CSF.
aggravated systemic proinflammatory responses, such as Activation of p38 MAPK is a primary factor in the
myocarditis. 11-13 induction of excessive inflammatory responses during other
Blood samples from vaccinated patients have revealed viral lung infections, such as highly pathogenic influenza
the persistence of vaccine-originated recombinant spike viruses. The activation of p38 MAPK phosphorylation and
protein. A specific spike fragment was found in 50% of downstream signal transduction through phospho-p38
the biological samples analyzed. The minimum time after activation of MSK-1 and NF-κB is the main route by which
vaccination that recombinant-spike was still detected in SARS-CoV-2 induces the expression of proinflammatory
vaccinated patients was 69 days, and the maximum time cytokines.
at which spike was still detected after vaccination was at In experimental systems, such as SARS-CoV-2 infection
least 187 days, evidence that many vaccinated individuals of Calu-3 cells or primary human lung explants or human

Volume 1 Issue 1 (2024) 2 doi: 10.36922/mi.2474