HLA-E01:01 + HLA-E01:01 Genotype Confers Less Susceptibility to COVID-19, While HLA-E01:03 + HLA-E01:03 Genotype is Associated with More Severe Disease

Overview

Journal Hum Immunol

Specialty Allergy & Immunology

Date 2023 Feb 23

PMID 36822912

Authors

Ehteramolsadat Hosseini

Arefeh Minagar

Mehran Ghasemzadeh

Ali Arabkhazaeli

Alireza Ghasemzadeh

Affiliations

Soon will be listed here.

Abstract

Background: HLA-E interaction with inhibitory receptor, NKG2A attenuates NK-mediated cytotoxicity. NKG2A overexpression by SARS-CoV-2 exhausts NK cells function, whereas virus-induced down-regulation of MHC-Ia reduces its derived-leader sequence peptide levels required for proper binding of HLA-E to NKG2A. This leads HLA-E to become more complex with viral antigens and delivers them to CD8 T cells, which facilitates cytolysis of infected cells. Now, the fact that alleles of HLA-E have different levels of expression and affinity for MHC Ia-derived peptide raises the question of whether HLA-E polymorphisms affect susceptibility to COVID-19 or its severity.

Methods: 104 COVID-19 convalescent plasma donors with/without history of hospitalization and 18 blood donors with asymptomatic COVID-19, all were positive for anti-SARS-CoV-2 IgG antibody as well as a group of healthy control including 68 blood donors with negative antibody were subjected to HLA-E genotyping. As a privilege, individuals hadn't been vaccinated against COVID-19 and therefore naturally exposed to the SARS-CoV-2.

Results: The absence of HLA-E*01:03 allele significantly decreases the odds of susceptibility to SARS-CoV-2 infection [p = 0.044; OR (95 %CI) = 0.530 (0.286 - 0.983)], suggesting that HLA-E*01:01 + HLA-E*01:01 genotype favors more protection against SARS-CoV-2 infection. HLA-E*01:03 + HLA-E*01:03 genotype was also significantly associated with more severe COVID-19 [p = 0.020; 2.606 (1.163 - 5.844) CONCLUSION: Here, our observation about lower susceptibility of HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19 could be clinical evidence in support of some previous studies suggesting that the lower affinity of HLA-E*01:01 to peptides derived from the leader sequence of MHC class Ia may instead shift its binding to virus-derived peptides, which then facilitates target recognition by restricted conventional CD8 T cells and leads to efficient cytolysis. On the other hand, according to other studies, less reactivity of HLA-E*01:01 with NKG2A abrogates NK cells or T cells inhibition, which may also lead to a greater cytotoxicity against SARS-CoV-2 infected cells compared to HLA-E*01:03. Taken together given HLA-E polymorphisms, the data presented here may be useful in identifying more vulnerable individuals to COVID-19 for better care and management. Especially since along with other risk factors in patients, having HLA-E*01:03 + HLA-E*01:03 genotype may also be associated with the possibility of severe cases of the disease.

Citing Articles

Associations Between Clinical Manifestations of SARS-CoV-2 Infection and HLA Alleles in a Caucasian Population: A Molecular HLA Typing Study.

Tymoniuk B, Borowiec M, Makowska J, Holwek E, Sarnik J, Styrzynski F J Clin Med. 2025; 13(24.

PMID: 39768617 PMC: 11676434. DOI: 10.3390/jcm13247695.

Exercise: a non-drug strategy of NK cell activation.

Pan H, Meng R, Jia Z, Zhang J, Ma W, Liu Y Braz J Med Biol Res. 2024; 57:e14144.

PMID: 39607207 PMC: 11653485. DOI: 10.1590/1414-431X2024e14144.

Non-Classical HLA Class 1b and Hepatocellular Carcinoma.

De Re V, Tornesello M, Racanelli V, Prete M, Steffan A Biomedicines. 2023; 11(6).

PMID: 37371767 PMC: 10296335. DOI: 10.3390/biomedicines11061672.

References

Araujo R, Bertol B, Cesar Dias F, Debortoli G, Almeida P, Souza F . HLA-E gene polymorphisms in chronic hepatitis C: Impact on HLA-E liver expression and disease severity. Hum Immunol. 2021; 82(3):177-185. DOI: 10.1016/j.humimm.2021.01.018. View

Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, Hertwig L . Natural killer cell immunotypes related to COVID-19 disease severity. Sci Immunol. 2020; 5(50). PMC: 7665314. DOI: 10.1126/sciimmunol.abd6832. View

Younas A, Waheed S, Khawaja S, Imam M, Borhany M, Shamsi T . Seroprevalence of SARS-CoV-2 antibodies among healthy blood donors in Karachi, Pakistan. Transfus Apher Sci. 2020; 59(6):102923. PMC: 7444608. DOI: 10.1016/j.transci.2020.102923. View

Slot E, Hogema B, Reusken C, Reimerink J, Molier M, Karregat J . Low SARS-CoV-2 seroprevalence in blood donors in the early COVID-19 epidemic in the Netherlands. Nat Commun. 2020; 11(1):5744. PMC: 7665189. DOI: 10.1038/s41467-020-19481-7. View

Ghasemzadeh M, Hosseini E, Schwarer A, Pourfathollah A . NK cell maturation to CD56(dim) subset associated with high levels of NCRs overrides the inhibitory effect of NKG2A and recovers impaired NK cell cytolytic potential after allogeneic hematopoietic stem cell transplantation. Leuk Res. 2016; 43:58-65. DOI: 10.1016/j.leukres.2015.12.002. View

Lam V, Lanier L . NK cells in host responses to viral infections. Curr Opin Immunol. 2016; 44:43-51. PMC: 5451301. DOI: 10.1016/j.coi.2016.11.003. View

Pietra G, Romagnani C, Manzini C, Moretta L, Mingari M . The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors. J Biomed Biotechnol. 2010; 2010:907092. PMC: 2896910. DOI: 10.1155/2010/907092. View

Kanevskiy L, Erokhina S, Kobyzeva P, Streltsova M, Sapozhnikov A, Kovalenko E . Dimorphism of HLA-E and its Disease Association. Int J Mol Sci. 2019; 20(21). PMC: 6862560. DOI: 10.3390/ijms20215496. View

Vidal S, Khakoo S, Biron C . Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol. 2011; 1(6):497-512. PMC: 3237675. DOI: 10.1016/j.coviro.2011.10.017. View

10.

Hosseini E, Kazerooni E, Azarkeivan A, Sharifi Z, Shahabi M, Ghasemzadeh M . HLA-E*01:01 allele is associated with better response to anti-HCV therapy while homozygous status for HLA-E*01:03 allele increases the resistance to anti-HCV treatments in frequently transfused thalassemia patients. Hum Immunol. 2022; 83(7):556-563. DOI: 10.1016/j.humimm.2022.04.010. View

11.

Ottenhoff T, Joosten S . Mobilizing unconventional T cells. Science. 2019; 366(6463):302-303. PMC: 6842658. DOI: 10.1126/science.aay7079. View

12.

Hammer Q, Dunst J, Christ W, Picarazzi F, Wendorff M, Momayyezi P . SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell Rep. 2022; 38(10):110503. PMC: 8858686. DOI: 10.1016/j.celrep.2022.110503. View

13.

Nattermann J, Nischalke H, Hofmeister V, Kupfer B, Ahlenstiel G, Feldmann G . HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells. Antivir Ther. 2005; 10(1):95-107. DOI: 10.1177/135965350501000107. View

14.

Henderson L, Canna S, Schulert G, Volpi S, Lee P, Kernan K . On the Alert for Cytokine Storm: Immunopathology in COVID-19. Arthritis Rheumatol. 2020; 72(7):1059-1063. PMC: 7262347. DOI: 10.1002/art.41285. View

15.

Pietra G, Romagnani C, Mazzarino P, Falco M, Millo E, Moretta A . HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes. Proc Natl Acad Sci U S A. 2003; 100(19):10896-901. PMC: 196899. DOI: 10.1073/pnas.1834449100. View

16.

Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T . Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018; 175(7):1731-1743.e13. PMC: 6292840. DOI: 10.1016/j.cell.2018.10.014. View

17.

Acter T, Uddin N, Das J, Akhter A, Choudhury T, Kim S . Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: A global health emergency. Sci Total Environ. 2020; 730:138996. PMC: 7190497. DOI: 10.1016/j.scitotenv.2020.138996. View

18.

Hosseini E, Schwarer A, Ghasemzadeh M . Do human leukocyte antigen E polymorphisms influence graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation?. Exp Hematol. 2014; 43(3):149-57. DOI: 10.1016/j.exphem.2014.11.007. View

19.

Ghasemzadeh M, Ghasemzadeh A, Hosseini E . Exhausted NK cells and cytokine storms in COVID-19: Whether NK cell therapy could be a therapeutic choice. Hum Immunol. 2021; 83(1):86-98. PMC: 8423992. DOI: 10.1016/j.humimm.2021.09.004. View

20.

Yaqinuddin A, Kashir J . Innate immunity in COVID-19 patients mediated by NKG2A receptors, and potential treatment using Monalizumab, Cholroquine, and antiviral agents. Med Hypotheses. 2020; 140:109777. PMC: 7194824. DOI: 10.1016/j.mehy.2020.109777. View

HLA-E*01:01 + HLA-E*01:01 Genotype Confers Less Susceptibility to COVID-19, While HLA-E*01:03 + HLA-E*01:03 Genotype is Associated with More Severe Disease

HLA-E01:01 + HLA-E01:01 Genotype Confers Less Susceptibility to COVID-19, While HLA-E01:03 + HLA-E01:03 Genotype is Associated with More Severe Disease