A moderate cytokine and chemokine response plays an indispensable role in the viral clearance and subsequent recovery while dysregulated response can bring devastating outcomes to infected cases [80]. A large number of immune cells, including macrophages, neutrophils, monocytes and lymphocytes, are migrated from bloodstream to infection site by the recruitment of hyperactive cytokines and chemokines, resulting in further release of high concentrations of various cytokines and chemokines and activation of immune cells, thereby underlying the basis of immune-mediated damages to hosts [72, 81]. The ways that SARS-CoV, MERS-CoV and SARS-CoV-2 cause histopathological injuries to infected cases are presented in Fig. 2. Briefly, these aforementioned hCoVs have been evolutionarily acquiring the ability to encode numerous proteins that allow them to evade from the host immune system, during which the delayed release of interferon plays a crucial role, then to attract and over-activate more inflammatory and immune cell, thereby inducing cytokine storm characterized by a massive secretion and hyper-activation of cytokines and chemokines until they have achieved sufficiently high titers [1, 80, 82], and finally to cause severe injury of infected tissues [81, 83]. Supporting evidence is abundant. The crucial roles of exaggerated pro-inflammatory cytokine and chemokine response resulted from infections of SARS-CoV and MERS-CoV in the exacerbation of SARS and MERS illnesses were firmly demonstrated [84]. Specifically, the delayed but excessive production of cytokines and chemokines was thought to be the induction of dysregulated innate immune response to SARS-CoV infection and poor outcomes on the basis of the fact that elevated serum levels and prolonged response of pro-inflammatory cytokines and chemokines were observed in SARS patients and were associated with the severity of SARS-CoV infection [28, 81]. Similar phenomena have been observed in patients infected by MERS-CoV, especially those who were severely infected, among whom numerous cytokines and chemokines were excessively activated, massive inflammatory and immune cells were promptly attracted and infiltrated in infected tissues, resulting in severe immunological injuries or even death [81, 85]. Likewise, the positive correlation between high pro-inflammatory cytokines and chemokines profile and the severity and outcomes of COVID-19 patients has been solidly confirmed, which indicates that SARS-CoV-2 infection also leads to hypercytokinemia or cytokine storm, by which ALI or ARDS and extrapulmonary multiple-organ failure or even death occur in infected cases [84, 86]. Similar to SARS, elevated levels of type 2 cytokines were also observed in COVID-19 [87, 88]. Although type 2 cytokines have anti-inflammation properties, and the expression of ACE2 was inhibited by them, surprisingly, they did not generate obvious benefits. This might be because type 2 cytokines simultaneously upregulated TMPRSS2 expression, which greatly negates their potential protective effects [89]. Overall, dysregulated cytokines and chemokines are associated with the progression and prognosis of infections caused by these hCoVs. Hence, interventions with these aberrant cytokines and chemokines might be promising for the managements of hCoVs-related diseases. Recently, many researchers are focused on the application of cytokine-based interventions, including immune inhibitors (such as inhibitors of IL-6, IFN-γ and TNF-α) in the therapy of COVID-19, and some of these inhibitors showed enthusiastic results (such as IL-6 inhibitor, siltuximab) [90, 91], however, more studies are needed to further investigate the therapeutic effects of these inhibitors.
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