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

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.

Keywords: CD8(+) T cell; Coronavirus disease 2019 (COVID-19); HLA-E; NK cell; NKG2A; Polymorphism; SARS-CoV-2; Susceptibility.

Fig. 1

HLA-E polymorphisms and CD8 + T cell function against SARS-CoV-2 infection. Decreased accessibility of HLA-E to its required peptide due to SARS-CoV-2-induced down-regulation of MHC-Ia expression may divert its binding to the viral peptides. The presentation of these peptides to HLA-E-restricted CD8 + T cells through TCR instead of NKG2A induces T cell mediated cytolytic effect against SARS-CoV-2 infected cells. Here, HLA-E*01:03 which was already shown to have higher cellular expression and more affinity to MHC class Ia derived peptides than HLA-E*01:01 may further support the NKG2A-depebdent inhibition of CD8 + T cells cytotoxicity against SARS-CoV-2 infected cells. In contrast, despite its lower expression, the possible higher affinity of HLA-E*01:01 to viral peptide and its presentation to HLA-E-restricted CD8 + T cells may induce its cytolytic activity against SARS-CoV-2 in a higher level than HLA-E*01:03. This may support the observed reduced susceptibility of individuals with HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19.

Fig. 2

HLA-E polymorphisms and NK cell function against SARS-CoV-2 infection. SARS-CoV-2 infection down-regulates the expression of classical MHC class Ia. This decreases HLA-E access to its natural peptides required for the interaction with inhibitory receptor NKG2A on NK cell. Alternatively, HLA-E can bind to viral peptides instead, and since its complex with SARS-CoV-2 antigen cannot interact with NKG2A, the inhibitory function of NK cells is abrogated while the resultant missing self-recognition allows more efficient cytolytic activation against infected cells. Here, compared to HLA-E*01:03, the lower expression of HLA-E*01:01 and its less affinity to peptide derived from the leader sequence of MHC class Ia, shifts this molecule to become more complex with viral peptides, which makes this ligand less reactive to NKG2A. This may favour less NK cells inhibition in individuals with HLA-E*01:01 + HLA-E*01:01 genotype, leading to more potent cytolytic effects against SARS-CoV-2 infected cells.