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Review
. 2022 Jan 1;18(2):459-472.
doi: 10.7150/ijbs.59272. eCollection 2022.

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

Yizhou Jiang  1 , Limor Rubin  2 , Tangming Peng  1 , Linlin Liu  1 , Xingan Xing  1 , Philip Lazarovici  3 , Wenhua Zheng  1
Affiliations
Review

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

Yizhou Jiang et al. Int J Biol Sci. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
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
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.
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