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Review
. 2021 Feb;476(2):675-687.
doi: 10.1007/s11010-020-03935-z. Epub 2020 Oct 16.

SARS-CoV-2 mediated lung inflammatory responses in host: targeting the cytokine storm for therapeutic interventions

Purva Asrani  1 , Md Imtaiyaz Hassan  2
Affiliations
Review

SARS-CoV-2 mediated lung inflammatory responses in host: targeting the cytokine storm for therapeutic interventions

Purva Asrani et al. Mol Cell Biochem. 2021 Feb.

Abstract

The recent exposure of novel coronavirus strain, severe acute respiratory syndrome (SARS-CoV-2) has spread to different countries at an alarming rate. Faster transmission rate and genetic modifications have provoked scientists to search for an immediate solution. With an increasing death rate, it becomes important to throw some light on the life cycle of the virus and its associated pathogenesis in the form of lung inflammation through cytokine storm (CS) production. This paper highlights the different stages of viral-mediated inflammatory responses in the host respiratory system. Previously, known anti-inflammatory drugs and therapeutic strategies that might show potential in controlling the CS of Coronavirus disease-2019 (COVID-19) is also mentioned in this study. Our critical analysis provides insights into the inflammation cycle induced in the lungs by early virus replication, downregulation and shedding of angiotensin-converting enzyme 2 (ACE2), and in the CS production. Identification of suitable targets within the inflammatory pathways for devising the therapeutic strategies useful in controlling the prognosis of COVID-19 finds a special mention in this article. However, antibody-dependent enhancement is the key aspect to consider before testing any drug/compound for therapeutic purposes. Our in-depth analysis would provide similarities and differences between the inflammatory responses induced by SARS-CoV and SARS-CoV-2, providing an excellent avenue to further look at how earlier outbreaks of coronaviruses were controlled and where new steps are required?

Keywords: And antibody-dependent enhancement; COVID-19; Cytokine storm; Lung inflammation; SARS-CoV-2; Therapeutic strategies.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Illustration of plans and highlights of the current study. Figure shows three major objectives of the study covered in this article and their associated key features summarizing the main findings
Fig. 2
Fig. 2
Immunopathogenesis initiated by SARS-CoV-2 replication in promoting the respiratory infection. The binding of SARS-CoV/SARS-CoV-2 on ACE2 of human lung cells causes increased viral uptake replication. This mediates apoptosis/pyroptosis of alveolar macrophages leading to the production of pro-inflammatory cytokines such as IL-1 β and TNF-α. These cytokines further perform three actions: mediates ACE2 downregulation and shedding leading to loss of RAS, increased TH17 cell activation causing further secretion of other pro-inflammatory cytokines and causing infiltration of innate immune cells. These immune cells can further cause production of pro-inflammatory cytokines (IL-1 β, TNF-α and IL-6) mediating TH17 cell function and leading to vascular permeability and leakage as the final steps of lung inflammation in the host cells post-viral attack. Abbreviations- Interleukin 1β (IL-1 β), Tumor necrosis factor (TNF-α), Interleukin 17 (IL-17), Interleukin 21 (IL-21), Interleukin 22 (IL-22), Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF), T helper cells (TH 17), Renin-angiotensin system (RAS)
Fig. 3
Fig. 3
A mechanism of TH 17 cell-mediated cytokine storm formation and immune responses in COVID-19 infected host. Binding of SARS-CoV-2 to ACE2 receptors of lung cells causes their endocytosis and further interaction with the alveolar macrophages triggering innate immunity. Apoptosis and pyroptosis of macrophages resulted in the production of IL-1β and TNF-α which activate TH17 cells for the production of pro-inflammatory cytokines, cytokine storm, and immune responses in the host system as described in the figure. The red arrow indicates the target area for the action of anti-inflammatory drugs (shown in orange boxes) that may be used in COVID-19 treatment. Abbreviations- Interleukin 1β (IL-1β), Tumor necrosis factor (TNF-α), Interleukin 17 (IL-17), Interleukin 21 (IL-21), Interleukin 22 (IL-22), Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF), T helper cells (TH 17)
Fig. 4
Fig. 4
Effect of JAK-2 and STAT-3 inhibitions in the regulation of TH17 cell differentiation and their consequences. a Shows the signaling of TH17 cells through the JAK-STAT pathway without the use of any inhibitors. Binding of IL-6 and IL-23 cytokines cause the dimerization of the receptor. This allows JAK-2 a receptor-bound enzyme to phosphorylate the tyrosine residues of the receptor for its activation. STAT-3 now interacts with the phosphorylated receptor with its SH2 domain and its dimerization occurs. The dimer travels to the nucleus and starts acting as a transcription factor. TH17 cell differentiation occurs through this mechanism leading to the formation of cytokine storm in COVID-19 patients. b Describes the effect of the JAK2 inhibitor on TH17 cell signaling. No phosphorylation of the receptors would occur in the absence of an active JAK2 and hence no STAT activation for transcription. TH17 cell differentiation could not occur and the patient may be cured for COVID-19 without the production of the cytokine storm. c Shows the effect of STAT-3 inhibitors on signaling of TH17 cells mediated by IL-6 and IL-23 ligands in the JAK-STAT pathway. Binding of IL-6 and IL-23 cytokines cause the dimerization of the receptor. This allows JAK-2 a receptor-bound enzyme to phosphorylate the tyrosine residues of the receptor for its activation. STAT-3 now interacts with the phosphorylated receptor with its SH2 domain. The use of inhibitors for STAT-3 now prevents STAT dimerization for acting as a transcription factor, as a result, no TH17 cell differentiation occurs through this mechanism, and no formation of cytokine storm in COVID-19 patients. d Describes the effect of STAT-3 inhibitors on B cell activation required for the antiviral immunity by IL-21 ligand in the JAK-STAT pathway. Binding of IL-21 cytokine causes the dimerization of the receptor. This allows JAK-1/3 a receptor-bound enzyme to phosphorylate the tyrosine residues of the receptor for its activation. STAT-3 now interacts with the phosphorylated receptor with its SH2 domain. The use of inhibitors for STAT-3 now prevents STAT dimerization for acting as a transcription factor, as a result, no B cell activation occurs through this mechanism, and no formation of immunity against SARS-CoV-2 infection. The red arrow indicates the target area for the action of drugs known as Fedritanib. (Shown in the orange box). Abbreviation: IL Interleukin, JAK Janus kinase, STAT signal transducer and activator of transcription, SH2 Src homology domain
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References

    1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. - PMC - PubMed
    1. Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17:181–192. - PMC - PubMed
    1. Stoecklin SB, Rolland P, Silue Y, Mailles A, Campese C, Simondon A, Mechain M, Meurice L, Nguyen M, Bassi C. First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures, January 2020. Eurosurveillance. 2020;25:2000094. - PMC - PubMed
    1. Weiss SR, Leibowitz JL (2011) Coronavirus pathogenesis. In: Advances in virus research. Elsevier, pp 85–164 - PMC - PubMed
    1. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, Si H-R, Zhu Y, Li B, Huang C-L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. - PMC - PubMed

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