3-1- Cytokines and chemokines
Cytokines and chemokines have been long considered to play an important
role in immunity and immunopathology during virus infections. A rapid
and well-coordinated innate immune response is the first line of defense
against viral infections. Conversely, dysregulated and excessive immune
responses may cause immunopathology (Channappanavar et al., 2016;
Davidson, Maini, & Wack, 2015; Shaw, Goldstein, & Montgomery, 2013).
Although there is no direct evidence for the involvement of
pro-inflammatory cytokines and chemokines in lung pathology during SARS
and MERS, correlative evidence from patients with severe disease
suggests a role for hyper-inflammatory responses in human coronavirus
(hCoV) pathogenesis (Channappanavar & Perlman, 2017).
Serum cytokine levels and analysis of lymphocyte composition suggests
that the SARS-CoV-2 infection is associated with lymphopenia
(particularly in CD4+ T cells and CD8+ T cells, but not in B cells),
overproduction of cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-2
receptor (IL-2R), IL-10, tumor necrosis factor-alpha (TNF-α), C-C motif
chemokine 2 (CCL2), CCL3, CCL5, and decreased IFN-γ-expression in CD4+ T
cells in severe COVID-19 cases, being correlated with the severity of
this disease. The levels of IL-6, IL-2R, IL-10, and TNF-α are mildly
elevated or within the normal range in moderate cases, but markedly
elevated in the most severe cases. These cytokines are probably produced
by highly inflammatory cells that have been implicated in a cytokine
storm (Chung Y Cheung et al., 2005; Griffith, Sokol, & Luster, 2014).
It is believed that dysregulated host immune response and cytokine storm
are correlated with disease severity and poor prognosis during SARS-CoV
and MERS-CoV infections (de Wit et al., 2016; Fehr, Channappanavar, &
Perlman, 2017; Newton, Cardani, & Braciale, 2016). An uncontrolled
systemic inflammation further results in illness severity. The
inflammatory cytokines, which may lead to activated T-helper-1(Th1) cell
responses, are unregulated (L. Chen et al., 2020; D. Wang et al., 2020).
However, SARS-CoV-2 patients exhibited excessive secretion of IL-4 and
IL-10 that may suppress inflammation via T-helper cell-2 (Th2) (C. Huang
et al., 2020) (Fig. 2).
While SARS-CoV productively infects airway and alveolar epithelial
cells, infection of hematopoietic cells such as dendritic cells (DCs),
monocyte-macrophages, and other peripheral blood mononuclear cells
(PBMCs) is abortive. SARS-CoV infection of DCs induces low-level
expression of antiviral cytokines IFN-α/β, moderate up-regulation of
pro-inflammatory cytokines TNF-α and IL-6, and a significant
up-regulation of inflammatory chemokines (C. Y. Cheung et al., 2005; Law
et al., 2005). Similarly, SARS-CoV-infected macrophages show delays in
secreting pro-inflammatory cytokines (Law et al., 2005). The delayed but
excessive production of these cytokines and chemokines is thought to
induce a dysregulated innate immune response to SARS-CoV infection. High
serum levels of pro-inflammatory cytokines and chemokines have been
observed in SARS patients with severe disease, compared to individuals
with uncomplicated SARS infections (Chien, Hsueh, Cheng, Yu, & Yang,
2006; C. H. Wang et al., 2005; Wong et al., 2004; Zhang et al., 2004).
These studies indicate that dysregulated and/or exaggerated cytokine and
chemokine responses by SARS-CoV infected airway epithelial cells, DCs,
and macrophages could play an important role in SARS pathogenesis.
Like SARS, MERS-CoV infection of human airway epithelial cells induces
significant but delayed IFN and proinflammatory cytokine (including
IL-1β, IL-6, and IL-8) responses (Lau et al., 2013). Interestingly, a
significant upregulation in the expression of IL-17 in MERS-CoV-infected
patients has been reported (Mahallawi, Khabour, Zhang, Makhdoum, &
Suliman, 2018). T helper cells, especially Th17 cells, produce the
proinflammatory cytokine IL-17 via the signal transducer and activator
of transcription–3 (STAT3) and NF-κB signaling pathways (Manni,
Robinson, & Alcorn, 2014). The MERS-CoV infection promotes the
induction of Th17 cytokines. These Th17 cytokines can recruit
neutrophils and monocytes to the site of infection or inflammation and
lead to the activation of other downstream cytokine and chemokine
cascades, such as IL1, IL6, TNF-α, Transforming growth factor-beta
(TGF-β), IL8, and Monocyte chemoattractant protein-1 (MCP-1) (Jin &
Dong, 2013).
It seems that the cytokine storm can initiate viral sepsis and
inflammatory-induced lung injury that leads to other related
complications such as pneumonitis, acute respiratory distress syndrome,
respiratory failure, shock, organ failure, and potentially death
(Prompetchara, Ketloy, & Palaga, 2020). It has been reported that
patients needing intensive care unit (ICU) had higher plasma levels of
various innate cytokines, IFN-γ-inducible protein 10 (IP-10), MCP-1,
macrophage inflammatory protein-1a (MIP-1a), and TNF-α, as clinical
features that have an association with disease progression and severity
(Mahallawi et al., 2018; Wong et al., 2004).