Page 33 - GTM-3-1

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

Secretion of inflammatory cytokines such as tumor necrosis this VOC. Serum antibodies from convalescent individuals
factor-alpha (TNF-α), interleukin (IL)-1, and IL-6 triggers (recovered from previous COVID-19 infection) were also
T cells. Consequently, cell-mediated immunity, controlled found futile, being four-fold less effective against Delta
by helper (CD4 ) and killer (CD8 ) T cells, is activated. The compared to the Alpha variant. In addition, along with
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cascade of stimulations initiated by helper T cells further the D614G and D950N mutations regulating S protein
activates and synchronizes the functions of other immune dynamics, the L452R mutation on the RBD also plays a
effector cells, such as macrophages and B cells. 15,16 However, vital part in antibody escape. The precise location of this
the release of pro-inflammatory cytokines can, on the mutation on the peripheral surface of the ACE-2 binding
contrary, be accountable for T cell exhaustion. Interaction area allows the virus to escape from antibodies while also
of TNF-α with tumor necrosis factor receptor 1 (TNFR1) enhancing its attachment to the ACE-2 receptor. This
receptor on T cells can direct T cells to undergo apoptosis. strategy of accumulating mutations in the peripheral
In addition, dysregulated secretion of IL-10 and IL-6 can region has significantly enhanced this variant’s ability to
also be responsible for a significant reduction of T cell evade host immunity. 24
numbers. A study reveals that over-secretion of TNF-α The disruption in host immunity is attributed to
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is also associated with substantial inhibition of Bcl-6 Tfh multiple factors. Viral NSP1 and NSP14 accomplish
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(follicular helper T lymphocytes) differentiation. This the translational shutdown of antiviral proteins. NSP8
phenomenon can render the outcomes of T cell-mediated B and NSP9 interfere with the Sec61-regulated pathway to
cell activation largely ineffective due to a significant loss of enter the endoplasmic reticulum, disrupting the whole
germinal center B cell formation. However, non-germinal process of host translation necessary for survival. Virus-
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B cells can thrive in this condition; yet, they are not efficient associated proteins also impede the secretion of IFN-I and
in providing long-term immunological memory or high- IFN-III. Proteins such as M protein, open reading frame
affinity B cells. Consequently, COVID-19 potentially (ORF) 3b, ORF6, and NSP13 inhibit the RIG-I/MDA-5–
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compromises both cell-mediated immunity and humoral MAVS pathway of cytosolic double-stranded RNA sensing,
immunity, thereby hindering effective IgG production as directly antagonizing IFN secretion. 25
well. 15
One of the key attributes of COVID-19 infection is the
3.2. Immune response during the Delta wave cytokine storm, characterized by severe dysregulation of
The VOC B.1.617.2, first identified in India toward the end cytokine response. This phenomenon has been associated
of 2020, was designated the Delta variant. By 2021, Delta with an elevated degree of pathogenicity in patients and
had claimed a significant number of lives. This strain has posed a serious challenge for clinicians and researchers
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proved to be far more contagious than its predecessor, alike. The release of pro-inflammatory cytokines such as
with a transmission rate estimated at around 40–60%, IL-1β, IL-2, IL-6, IL-10, TNF-α, IFN-γ, and granulocyte
posing a heightened risk to the populations with partial macrophage-colony stimulating factor is commonly
or no vaccination. Statistics revealed approximately observed in this scenario.
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st
400,000 cases and 4000 mortalities within the 1 weeks According to studies, discord in the timing of
of May 2021 in India alone, with subsequent spread to appropriate immune responses is implicated in the
over 40 countries across various continents. The major development of a cytokine storm in a patient. During the
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mutation in the spike protein contributing to its increased early phases of infection, the host body fails to produce
transmissibility and evasion of antibody neutralization was potent IFNs (I and III) effectively to combat the pathogen
D614G. In contrast to Delta, the Alpha and Beta strains while simultaneously continuing to secrete IL-6 and other
exhibited an N501Y substitution. 22 chemokines. This failure to produce IFNs and continued
Previous variants mutations had mutations clustered secretion of IL-6 and other chemokines creates a conducive
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in the N-terminal domain (NTD), which proved to be environment for a pro-inflammatory response. The role
sensitive targets for human monoclonal antibodies (mAbs). of IL-6 remains relevant during the Delta wave, as reports
These mAbs were highly effective in neutralizing the virus, indicate elevated levels of IL-6 correlating with disease
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inhibiting the cell-cell fusion method of infection, and severity. This phenomenon facilitates viral replication and
stimulating the host’s effector functions, making them the progression of infection. As the infection progresses,
promising targets for therapeutic interventions. However, by the time the body regains its ability to mount a defense,
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a critical study has elucidated the ineffectiveness of the infection load has already heightened, prompting an
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monoclonal antibodies against the Delta strain. Both anti- exaggerated and uncontrolled immune response.
NTD and anti-RBD mAbs classes failed to bind effectively A balanced response of Th1 and Th2 cytokines is
to the Delta spike protein and were unable to neutralize desirable. Immune exaggeration is a consequence of the

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