Cytokine storm in COVID-19: from viral infection to immune responses, diagnosis and therapy

Abstract

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; cytokines; diagnosis; immune response; therapy; vaccination.

Figure 1

Mechanism of SARS-CoV-2 viral entry. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its cellular receptor. The cell entry of SARS-CoV-2 is also dependent on transmembrane protease serine 2 (TMPRSS2), Neuropilin-1 (NRP1) and cathepsin B and L (CatB/L).

Figure 2

Proposed mechanisms of COVID-19 -induced cytokine storm. SARS-CoV-2 can directly activate the key inflammation regulator NF-kB via pattern recognition receptors (PPRs). ACE2 downregulation caused by shedding and internalization of ACE2 leads to increased angiotensin II (AngII) levels and hyperactivation of NF-kB, followed by excessive proinflammatory cytokine production. AngII can stimulate both shedding and internalization of ACE2, representing a positive feedback mechanism in the renin-angiotensin system. In addition, AngII can also promote the shedding of molecules that can activate NF-kB including TNFα, sIL-6Rα and EGFR ligands. These positive feedback mechanisms may further enhance the proinflammatory cytokine production and lead to a cytokine storm.