Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein.
Front Immunol
; 13: 996637, 2022.
Article
in English
| MEDLINE | ID: covidwho-2043454
ABSTRACT
Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection remains elusive. In this study, we showed that Dok3 adaptor restrains calprotectin production by neutrophils in response to SARS-CoV-2 spike (S) protein engagement of TLR4. Dok3 recruits SHP-2 to mediate the de-phosphorylation of MyD88 at Y257, thereby attenuating downstream JAK2-STAT3 signaling and calprotectin production. Blocking of TLR4, JAK2 and STAT3 signaling could prevent excessive production of calprotectin by Dok3-/- neutrophils, revealing new targets for potential COVID-19 therapy. As S protein from SARS-CoV-2 Delta and Omicron variants can activate TLR4-driven calprotectin production in Dok3-/- neutrophils, our study suggests that targeting calprotectin production may be an effective strategy to combat severe COVID-19 manifestations associated with these emerging variants.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Adaptor Proteins, Signal Transducing
/
Spike Glycoprotein, Coronavirus
/
COVID-19
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Front Immunol
Year:
2022
Document Type:
Article
Affiliation country:
Fimmu.2022.996637
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