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Article

Immunophenotyping and Functional Characterization of NK Cells in SARS-CoV-2 Infection

by
Steliyan Petrov
1,*,
Martina Bozhkova
1,
Mariya Ivanovska
1,
Teodora Kalfova
1,
Alexandra Baldzhieva
1,
Angel Todev
2,
Dilyana Kirova
3,
Yoana Kicheva
3,
Stoyno Stoynov
3,
Marianna Murdjeva
1 and
Hristo Taskov
1
1
Department of Medical Microbiology and Immunology “Prof. Dr. Elissay Yanev”, and Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
2
Infectious Diseases Clinic, University Hospital “St. George”,4000 Plovdiv, Bulgaria
3
Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl. 21, 1113 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Immuno 2025, 5(3), 35; https://doi.org/10.3390/immuno5030035
Submission received: 23 June 2025 / Revised: 9 August 2025 / Accepted: 11 August 2025 / Published: 15 August 2025
(This article belongs to the Section Innate Immunity and Inflammation)
Review Reports Versions Notes

Abstract

The immune response to SARS-CoV-2 infection involves significant alterations in the phenotype and function of natural killer (NK) cells. This study aimed to investigate the dynamic changes in NK cell subsets during COVID-19 by analyzing their activation and inhibitory markers [CD3, CD14, CD16, CD19, CD25, CD45, CD56, CD57, CD69, CD159a (NKG2A), CD159c (NKG2C), CD314 (NKG2D), CD335 (NKp46)], cytotoxic potential (perforin, interferon-gamma, granzyme B), and direct cytotoxicity against a newly genetically modified K562 cell line. Peripheral blood samples were collected from COVID-19 patients on days 3–5 and day 30 post-symptom onset and were compared to healthy controls. 16-color flow cytometry analysis revealed distinct shifts in NK cell subpopulations, characterized by increased expression of the inhibitory receptor NKG2A and the activating receptors NKG2D and NKG2C, particularly in the CD56+CD16− subset. Elevated IFN-γ production on day 30 suggested a recovery-phase immune response, while the persistent upregulation of NKG2A indicated an ongoing regulatory mechanism. The CD16+CD56− subpopulation exhibited increased expression of the markers CD69 and CD25 over time; however, its cytotoxic potential, assessed through granzyme B levels and direct cytotoxicity assays, remained lower than that of healthy controls. Significant correlations were observed between CD57 and CD69 expression, as well as NKp46 and IFN-γ production, highlighting a coordinated balance between activation and regulatory mechanisms. These findings suggest that NK cells undergo functional adaptation during COVID-19, displaying signs of partial exhaustion while retaining antiviral potential. Understanding the interplay between NK cell activation and suppression may provide valuable insights into immune dysregulation in COVID-19 and inform potential therapeutic interventions.
Keywords: natural killer cells; COVID-19; SARS-CoV-2; flow cytometry; immune response; immune dysregulation natural killer cells; COVID-19; SARS-CoV-2; flow cytometry; immune response; immune dysregulation

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MDPI and ACS Style

Petrov, S.; Bozhkova, M.; Ivanovska, M.; Kalfova, T.; Baldzhieva, A.; Todev, A.; Kirova, D.; Kicheva, Y.; Stoynov, S.; Murdjeva, M.; et al. Immunophenotyping and Functional Characterization of NK Cells in SARS-CoV-2 Infection. Immuno 2025, 5, 35. https://doi.org/10.3390/immuno5030035

AMA Style

Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Baldzhieva A, Todev A, Kirova D, Kicheva Y, Stoynov S, Murdjeva M, et al. Immunophenotyping and Functional Characterization of NK Cells in SARS-CoV-2 Infection. Immuno. 2025; 5(3):35. https://doi.org/10.3390/immuno5030035

Chicago/Turabian Style

Petrov, Steliyan, Martina Bozhkova, Mariya Ivanovska, Teodora Kalfova, Alexandra Baldzhieva, Angel Todev, Dilyana Kirova, Yoana Kicheva, Stoyno Stoynov, Marianna Murdjeva, and et al. 2025. "Immunophenotyping and Functional Characterization of NK Cells in SARS-CoV-2 Infection" Immuno 5, no. 3: 35. https://doi.org/10.3390/immuno5030035

APA Style

Petrov, S., Bozhkova, M., Ivanovska, M., Kalfova, T., Baldzhieva, A., Todev, A., Kirova, D., Kicheva, Y., Stoynov, S., Murdjeva, M., & Taskov, H. (2025). Immunophenotyping and Functional Characterization of NK Cells in SARS-CoV-2 Infection. Immuno, 5(3), 35. https://doi.org/10.3390/immuno5030035

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