Page 34 - GTM-3-1

Global Translational Medicine Immune response in humans due to COVID-19 infection

upregulation of Th2 activity, while polarization toward and BA.5) circulating within the population, the Omicron
Th1 activity can tactfully perform viral clearance. 29-31 The variant, in general, is associated with the highest degree
Th2 cytokine IL-10 potentially impedes the functionality of neutralizing antibody escape due to a heavy load of
of the Th1 subset and results in poor convalescence in mutations on its spike protein. Omicron was first
1,39
patients. 21,29 However, some studies found that, as an anti- recorded in Botswana, Southern Africa, and it exhibited
inflammatory cytokine, deficiency of IL-10 led to increased 32 amino acid mutations in the spike protein. Reports
disease severity in patients. Thus, the role of IL-10 in the observed that BA.1 and BA.2 display the highest level of
orchestration of the cytokine storm remains fuzzy due to escape from neutralization by host antibodies compared to
contradictory reports, and comprehensive quantification any other sarbecoviruses, with mutations such as G339D,
of other cytokines involved could help clinicians better S371L/F, S373P, S375F, R408S, and D406N. 1
understand the disease. Both IL-10 and IL-4 allow The emergence of this variant marks a significant
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the degranulation and aggregation of eosinophils and turning point in the immunological scenario of the
basophils in the lungs, causing severe impairment of the
alveoli. 8,21,31,33 The final outcome of alveolar congestion and pandemic. The genomic changes associated with this
capillary hemorrhage becomes consolidation of the lungs. 34 variant are deeply related to evolutionary circumstances,
and the manifestation of these alterations has been
Focusing on the damage of cell-mediated immunity, it responsible for a significant shift in the host-virus
is crucial to shed light on antigen presentation and immune paradigm. Taking note of the evolutionary point, bats serve
surveillance. Viral infection signals or presents itself to as the reservoir host for many sarbecoviruses. As reservoirs,
CD8 T cells through major histocompatibility complex-I bats develop an appropriate IFN-rich environment to
+
(MHC-I) molecules. On recognition of the antigenic defend themselves against sarbecovirus infection, which
peptides, the infected host cell is targeted for destruction primes sarbecoviruses for IFN attack. Since humans lack
using perforins, granzymes, and Fas ligand (FasL), which such constitutive immune environments, infection with
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are released by the CD8 T cells. As this pathway is vital bat sarbecoviruses can overwhelm the human host’s IFN
+
for precise viral eradication, the downregulation of antigen response. This environmental discrepancy in the human
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presentation remains an attractive target for SARS-CoV-2 host has facilitated the evolution of the Omicron variant
infection. Studies have discovered that fighting against in a manner distinct from its ancestral sarbecoviruses,
COVID-19 becomes even more challenging in the acquiring a significant degree of neutralizing antibody
presence of dampened MHC-I regulation, which occurs escape. 1
under the effect of ORF8 viral protein through autophagy
pathways. Cells exposed to ORF8 become more resistant The Omicron variant, in addition to its adeptness
to cytotoxic lysis, while cells with knocked-down ORF8 in evading immune responses, exhibits very high
become sensitive to cytotoxicity. ORF8 selectively targets transmissibility, which is considered a vital evolutionary
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MHC-I for lysosomal degradation in an autophagy- event during the pandemic. The evasion pathway of
mediated pathway, where ORF8 attaches to MHC-I Omicron differs significantly from that of Delta and Alpha
molecules and directs them toward autophagosomes or variants, suggesting the possibility of a host-jumping
lysosomes. However, a report has been published stating event occurring amidst the pandemic. Initially, it was
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the failure of ORF8 to downregulate MHC-I in the case hypothesized that Omicron either spread cryptically
of the Delta variant. Deletion mutations such as Asp119 within the human population or might have evolved in
and Phe120 in the Delta variant impair ORF8 dimer patients with compromised immune systems. However, a
formation and structural instability, leading to poor recent study dismisses other hypotheses and reveals that
affinity toward MHC-I molecules. The presence of these the mutations observed in the progenitor of Omicron most
mutations indicates better host adaptation in presenting likely occurred in a cell of a mouse rather than humans. This
the SARS-CoV-2 antigen. In silico studies also support phenomenon suggests a scenario where the progenitor of
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this phenomenon by surmising the impact of the Delta Omicron infected a mouse, acquired significant mutations,
variant on allele-specific-HLA-peptide-binding affinity, and then jumped back to human hosts, evolving into the
which has occurred in a diminished manner due to a heavy Omicron variant. Thus, interspecific evolution has affected
load of mutations. 38 the mode of invasion of human host cells. In contrast
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to prevailing strains where the virus targets the ACE-2
3.3. Immune response during the Omicron wave receptor as a key to access host cells, Omicron adopts
The Omicron variant (B.1.1.529) has become a significant an endosomal mode of entry, neglecting the function of
global concern in the later stages of the pandemic. Despite TMPRSS2 protease. The pathway of endosomal fusion
the presence of five sub-lineages (BA.1, BA.2, BA.3, BA.4, is probably facilitated by a geometric restructuring of

Volume 3 Issue 1 (2024) 4 https://doi.org/10.36922/gtm.2228