The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Coordinated innate and T-cell immune responses in mild COVID-19 patients from household contacts of COVID-19 cases during the first pandemic wave

“…The up-regulated levels of IP-10, IL-1ra and MCP-1 observed in swab positive subjects are supported also by other findings showing that the levels of these cytokines/chemokines are prominent during the second week after disease onset and are even more pronounced in severe patients ( 19 , 58 , 59 ). The pro-inflammatory chemokine IP-10 and the monocyte chemoattractant factor MCP-1 contribute to the excessive inflammatory and immune response, favoring the recruitment of monocytes, macrophages, and T cells to the infection sites.…”

“…The lower levels of the pro-inflammatory factors IL-1b, RANTES and MIP-1b, and of IL-9, a cytokine with direct and indirect effects on multiple cell types that affect the development of immunity and inflammation, may be indicative in our study cohort of a controlled inflammatory process, in which the IL-1ra exerts an effective action. Indeed, a higher production of IL-1b, RANTES, MIP-1b and IL-9 have been found in the severe disease (18,59,62). The differences, in terms of cytokine amount, observed between swab positive and negative subjects in our cohort are highly significant (at least p=0.007) for certain immune factors (IFN-a, IL-1ra, IP-10, IL-9 and MIP-1b).…”

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients

“…They are classified into four groups according to the first two locations of cysteine in their protein sequences: the CC-, CXC-, C- and CX3C-chemokine families. Chemokines are extremely redundant, with many ligands binding to the same receptor, and vice versa [ 20 ]. Chemokines are essential in the amplification of inflammatory responses, the initial recruitment of cells of the innate immune system, and then that of cells of the adaptive immune system.…”

Mechanisms of host type I interferon response modulation by the nucleocapsid proteins of alpha- and betacoronaviruses

“…The inflammasome is a multiprotein complex that induces the expression of pro-inflammatory mature IL-1β and IL-18, as well as pyroptotic cell death [ 18 ]. While inflammation is protective against virus infections, uncontrolled inflammation has been documented to contribute to viral pathogenesis, such as severe COVID-19 disease after SARS-CoV-2 infection [ 19 ]. In this regard, SARS-CoV-2 N protein has been shown to induce NLRP3 inflammasome assembly through direct binding to NLRP3, resulting in hyperinflammation [ 20 ].…”