The immunopathogenesis of a cytokine storm: The key mechanisms underlying severe COVID-19

Abstract

A cytokine storm is marked by excessive pro-inflammatory cytokine release, and has emerged as a key factor in severe COVID-19 cases – making it a critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients’ immune systems then fail to shift from innate to adaptive immunity, suppressing interferon responses and leading to excessive pyroptosis and neutrophil activation. This amplifies tissue damage and inflammation, creating a pro-inflammatory loop. The result is the disruption of Th1/Th2 and Th17/Treg balances, lymphocyte exhaustion, and extensive blood clotting. Cytokine storm treatments include glucocorticoids to suppress the immune system, monoclonal antibodies to neutralize specific cytokines, and JAK inhibitors to block cytokine receptor signalling. However, the most effective treatment options for mitigating SARS-CoV-2 infection remain vaccines as a preventive measure and antiviral drugs for the early stages of infection. This article synthesizes insights into immune dysregulation in COVID-19, offering a framework to better understand cytokine storms and to improve monitoring, biomarker discovery, and treatment strategies for COVID-19 and other conditions involving cytokine storms. After SARS-CoV-2 infection, disrupted angiotensin signalling, delayed interferon response and inflammasome-driven pyroptosis contribute to the development of cytokine storm. Once present, it causes extensive inflammation and thrombosis contributing to tissue and organ damage, whilst at the same hindering efficient viral clearance, complicating patient recovery and thus leading to severe Covid-19. • Multiple factors are responsible for cytokine storm development in COVID-19 patients • Inefficient activation of adaptive immunity is critical for patient deterioration • Pathological levels of IL-1, IL-6 and TNF-α are behind major clinical manifestations • Current treatments for severe COVID-19 patients are only partially effective

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