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).