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Genetic Variability in NKG2 Receptors and Their Ligands: Associations with SARS-CoV-2 Infection and COVID-19 Severity

Jagoda Siemaszko1, Katarzyna Grad1, Jerzy Świerkot2

  • 1Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland.

Genes
|October 29, 2025
PubMed
Abstract

Insights

Genetic variations in Natural Killer (NK) cell receptors and their ligands are linked to COVID-19 risk and symptom severity. Specific alleles and soluble protein levels influence disease outcomes in SARS-CoV-2 infection.

Area of Science:

  • Immunology
  • Genetics
  • Infectious Diseases

Background:

  • COVID-19 pandemic spurred research into immune responses.
  • Natural Killer (NK) cell cytotoxic activity is regulated by activating and inhibitory receptors.
  • NKG2 family receptors are crucial for NK cell function and cytotoxicity control.

Purpose of the Study:

  • To investigate the genetic variability of NKG2A, NKG2D, HLA-E, MICA/MICB, and NKG2C deletion.
  • To assess the association between genetic polymorphisms and serum-soluble levels of these molecules with COVID-19 risk and severity.

Main Methods:

  • Quantitative PCR (qPCR) for single-nucleotide polymorphisms (SNPs) in NKG2A, NKG2D, MICA/MICB.
  • PCR-SSP for NKG2C deletion.
  • ELISA and Luminex assays for serum-soluble HLA-E and MICA/MICB levels.

Main Results:

  • Predominant NKG2A and HLA-E alleles found in infected individuals.
  • MICA allele (129Met) common in hospitalized patients.
  • NKG2C deletion associated with increased SARS-CoV-2 infection risk.
  • Elevated serum-soluble MICB levels in infected individuals.

Conclusions:

  • Genetic variability in NK cell receptors and ligands correlates with COVID-19 susceptibility.
  • Serum levels of soluble NK cell receptor ligands are associated with COVID-19 severity.
  • These findings highlight the role of NK cell-mediated immunity in SARS-CoV-2 infection.
Keywords:
COVID-19HLA-ENK cell receptorsNK cellsNKG2CSARS-CoV-2viral infection

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