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High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19.
Vietzen, Hannes; Danklmaier, Vera; Zoufaly, Alexander; Puchhammer-Stöckl, Elisabeth.
  • Vietzen H; Center for Virology, Medical University of Vienna, Vienna, Austria. Electronic address: hannes.vietzen@meduniwien.ac.at.
  • Danklmaier V; Center for Virology, Medical University of Vienna, Vienna, Austria.
  • Zoufaly A; Department of Medicine IV, Clinic Favoriten, Vienna, Austria; Faculty of Medicine, Sigmund Freud University, Vienna, Austria.
  • Puchhammer-Stöckl E; Center for Virology, Medical University of Vienna, Vienna, Austria.
Genet Med ; 24(7): 1449-1458, 2022 07.
Article in English | MEDLINE | ID: covidwho-1991046
ABSTRACT

PURPOSE:

Host genetic variants in activating natural killer (NK) cell receptors may contribute to differences in severity of COVID-19. NK cell-mediated antibody-mediated cellular cytotoxicity (ADCC) responses play, however, a controversial role in SARS-CoV-2 infections. It is unclear whether proinflammatory and cytotoxic SARS-CoV-2-specific ADCC responses limit disease severity or rather contribute to the immunopathogenesis of severe COVID-19.

METHODS:

Using a genetic association approach and subsequent in vitro antibody-dependent NK cell activation experiments, we investigated whether genetic variants in the FcγRIIIa-encoding FCGR3A gene, resulting in expression of either a low-affinity or high-affinity variant, and individual SARS-CoV-2-specific ADCC response contribute to COVID-19 severity.

RESULTS:

In our study, we showed that the high-affinity variant of the FcγRIIIa receptor, 158-V/V, is significantly over-represented in hospitalized and deceased patients with COVID-19, whereas the low-affinity FcγRIIIa-158-F/F variant occurs more frequently in patients with mild COVID-19 (P < .0001). Furthermore, functional SARS-CoV-2 antibody-specific NK cell-mediated ADCC assays revealed that significantly higher proinflammatory ADCC responses occur in hospitalized patients with COVID-19, and are especially observed in NK cells expressing the FcγRIIIa-158-V/V variant (P < .0001).

CONCLUSION:

Our study provides evidence that pronounced SARS-CoV-2-specific NK cell-mediated ADCC responses are influenced by NK cell FcγRIIIa genetic variants and are a hallmark of severe COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Antineoplastic Agents Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Genet Med Journal subject: Genetics, Medical Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Antineoplastic Agents Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Genet Med Journal subject: Genetics, Medical Year: 2022 Document Type: Article