Skip to main content
SpringerLink
Log in

Association of inhibitory NKG2A and activating NKG2D natural killer cell receptor genes with resistance to SARS-CoV-2 infection in a western Indian population

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

We have evaluated the association of polymorphisms in the intronic variable-number tandem repeat (VNTR) regions of the human NKG2D, NKG2A, and IL-1RN genes with resistance and/or susceptibility to SARS-CoV-2 infection in a total of 209 patients with SARS-CoV-2 infection (125 asymptomatic patients and 84 symptomatic patients with mild symptoms) and 355 healthy controls, using the PCR-RFLP method. The genotypic and allelic frequency distributions for an IL-1RN (VNTR) single-nucleotide polymorphism (SNP) were found to be comparable among the patient groups. Overall, in SARS-CoV-2 patients, NKG2A (rs2734440) showed a protective association in the codominant [(A/A vs. A/G): (OR = 0.53, 95% CI = 0.34–0.83, p = 0.006)], recessive [(A/A vs. A/G+G/G): (OR = 0.6, 95% CI = 0.39–0.92, p = 0.02)] and over-dominant [(A/A+G/G vs. A/G): (OR = 0.57, 95% CI = 0.38–0.84, p = 0.005)] models. Similarly, NKG2D (rs7980470) showed a protective association in the codominant [(A/A vs. A/G): (OR = 0.46, 95% CI = 0.3–0.7, p = 0.0003), codominant (A/A vs. G/G): (OR = 0.54, 95% CI = 0.31–0.71, p = 0.027)], recessive [(A/A vs. A/G+G/G): (OR = 0.47, 95% CI = 0.32–0.7, p = 0.0001) and over-dominant [(A/A+G/G vs. A/G): (OR = 0.56, 95% CI = 0.38–0.82, p = 0.003)] models. At the allelic level, there was a higher frequency of the “G” allele of NKG2D (rs7980470) in healthy controls than in patients with SARS-CoV-2 infection, suggesting that individuals with the “G” allele in the intronic region of NKG2D are likely to be protected against SARS-CoV-2 infection. Overall, our data suggest that polymorphisms in the host NKG2D and NKG2A genes have a protective role in SARS-CoV-2 infection, although the functional impact of these polymorphisms on control of SARS-CoV-2 infection remains unknown.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The original data presented in the study are included in the article. Further detail/inquiries can be directed to the corresponding author.

References

  1. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W et al (2020) Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75(7):1564–1581. https://doi.org/10.1111/all.14364

    Article  CAS  PubMed  Google Scholar 

  2. Wang F, Nie J, Wang H, Zhao Q, Xiong Y et al (2020) Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis 221(11):1762–1769. https://doi.org/10.1093/infdis/jiaa150

    Article  CAS  PubMed  Google Scholar 

  3. Alagarasu K, Honap T, Mulay P, Bachal V, Shah S et al (2012) Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection. Hum Immunol 73(11):1194–1199. https://doi.org/10.1016/j.humimm.2012.08.007

    Article  CAS  PubMed  Google Scholar 

  4. Tripathy AS, Ganu A, Sonam L, Alagarasu K, Walimbe M et al (2019) Association of IL1RN VNTR polymorphism with chikungunya infection: a study from Western India. J Med Virol 91(11):1901–1908. https://doi.org/10.1002/jmv.25546

    Article  CAS  PubMed  Google Scholar 

  5. Costela-Ruiz I-M, Puerta-Puerta R, Melguizo-Rodríguez L (2020) SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Fact Rev 54:62–75. https://doi.org/10.1016/j.cytogfr.2020.06.001

    Article  CAS  Google Scholar 

  6. Tripathy AS, Vishwakarma S, Trimbake D, Gurav K, Potdar V, Mokashi N (2021) Pro-inflammatory CXCL-10, TNF-α, IL-1β, and IL-6: biomarkers of SARS-CoV-2 infection. Adv Virol 166:3301–3310. https://doi.org/10.1007/s00705-021-05247-z

    Article  CAS  Google Scholar 

  7. Di Vito C, Calcaterra F, Coianiz N, Terzoli S, Voza A, Mikulak J et al (2022) Natural killer cells in SARS-CoV-2 infection: pathophysiology and therapeutic implications. Front Immunol. https://doi.org/10.3389/fimmu.2022.888248

    Article  PubMed  PubMed Central  Google Scholar 

  8. Harrison J, Ettorre A, Khakoo S (2010) Association of NKG2A with treatment for chronic hepatitis C virus infection. Clin Exp Immunol 161(2):306–314. https://doi.org/10.1111/j.1365-2249.2010.04169.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iwaszko M, Świerkot J, Kolossa K, Jeka S, Wiland P, Bogunia-Kubik K (2018) Influence of NKG2D genetic variants on response to anti-TNF agents in patients with rheumatoid arthritis. Genes 9(2):64. https://doi.org/10.3390/genes9020064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tripathy AS, Trimbake D, Suryawanshi P, Tripathy S, Gurav Y, Potdar V (2022) Peripheral lymphocyte subset alteration in patients with COVID-19 having differential clinical manifestations. Indian J Med Res 155(1):136–147. https://doi.org/10.4103/ijmr.IJMR_453_21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tarlow J, Blakemore A, Lennard A, Solari R, Hughes H, Steinkasserer A, Duff G (1993) Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 91:403–404. https://doi.org/10.1007/BF00217368

    Article  CAS  PubMed  Google Scholar 

  12. Ma J, Guo X, Wu X, Li J, Zhu X et al (2010) Association of NKG2D genetic polymorphism with susceptibility to chronic hepatitis B in a Han Chinese population. J Med Virol 82(9):1501–1507. https://doi.org/10.1002/jmv.21855

    Article  CAS  PubMed  Google Scholar 

  13. Paim A, Lopes-Ribeiro A, e Silva D, Andrade L, Moraes T et al (2021) Will a little change do you good? A putative role of polymorphisms in COVID-19. Immunol Lett 235:9–14. https://doi.org/10.1016/j.imlet.2021.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Conti P, Dempsey RA, Reale M, Barbacane RC, Panara MR (1991) Activation of human natural killer cells by lipopolysaccharide and generation of interleukin-1 alpha, beta, tumour necrosis factor and interleukin-6. Effect of IL-1 receptor antagonist. Immunology 73(4):450

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen C, Yang S, Liu C, Lin C, Liaw Y et al (2005) Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma. Int J Epidemiol 34(6):1310–1318. https://doi.org/10.1093/ije/dyi191

    Article  PubMed  Google Scholar 

  16. Witkin S, Gerber S, Ledger W (2002) Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 34(2):204–209. https://doi.org/10.1086/338261

    Article  CAS  PubMed  Google Scholar 

  17. Suryawanshi P, Takbhate B, Athavale P, Jali P, Memane N et al (2023) Lymphopenia with altered T Cell subsets in hospitalized COVID-19 patients in Pune, India. Viral Immunol 36(3):163–175

    CAS  PubMed  Google Scholar 

  18. Demaria O, Carvelli J, Batista L, Thibult ML, Morel A et al (2020) Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19. Cell Mol Immunol 17(9):995–997

    Article  CAS  PubMed  Google Scholar 

  19. Lee MJ, Leong MW, Rustagi A, Beck A, Zeng L et al (2022) SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D. Cell Rep 41(13):111892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gunturi A, Berg RE, Forman J (2004) The role of CD94/NKG2 in innate and adaptive immunity. Immunol Res 30:29–34

    Article  CAS  PubMed  Google Scholar 

  21. Bauer S, Groh V, Wu J, Steinle A, Phillips J et al (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285(5428):727–729. https://doi.org/10.1126/science.285.5428.727

    Article  CAS  PubMed  Google Scholar 

  22. Obeidy P, Sharland A (2009) NKG2D and its ligands. Int J Biochem Cell Biol 41(12):2364–2367. https://doi.org/10.1016/j.biocel.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  23. Jamieson A, Diefenbach A, McMahon C, Xiong N, Carlyle J et al (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17(1):19–29. https://doi.org/10.1016/S1074-7613(02)00333-3

    Article  CAS  PubMed  Google Scholar 

  24. Burgess S, Maasho K, Masilamani M, Narayanan S, Borrego F et al (2008) The NKG2D receptor: immunobiology and clinical implications. Immunol Res 40:18–34

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Mr. Vasant Walkoli, Mr. K.D. Ramaiah, Mr. Bipin Tilekar and Mr PD Sarje for their genuine effort in clinical sample collection for the study. Financial support provided by the Indian Council of Medical Research, New Delhi, is duly acknowledged.

Author information

Authors and Affiliations

  1. Department of Dengue and Chikungunya, Indian Council of Medical Research-National Institute of Virology, 20-A, Dr Ambedkar Road, Pune, Maharashtra, 411 001, India

    Anuradha S. Tripathy, Priyanka Wagh, Kadambari Akolkar, Atul M. Walimbe, Varsha A. Potdar, Manohar Lal Choudhary & Priya Abraham

  2. BJMC and Sassoon General Hospital, Pune, Maharashtra, India

    Nalini Kadgi & Leena Nakate

Authors
  1. Anuradha S. Tripathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priyanka Wagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kadambari Akolkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atul M. Walimbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Varsha A. Potdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manohar Lal Choudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nalini Kadgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leena Nakate
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Priya Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: AST. Material preparation, data collection and analysis: PW, KA, AMW. Resources: VAP, MC, NK, LN. Writing—original draft preparation: AST, KA. PW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Anuradha S. Tripathy.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial conflicts of interest to disclose.

Additional information

Handling Editor: Tim Skern.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tripathy, A.S., Wagh, P., Akolkar, K. et al. Association of inhibitory NKG2A and activating NKG2D natural killer cell receptor genes with resistance to SARS-CoV-2 infection in a western Indian population. Arch Virol 168, 237 (2023). https://doi.org/10.1007/s00705-023-05861-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00705-023-05861-z

Search

Navigation