tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2023 Feb 27;2185467.
doi: 10.1080/22221751.2023.2185467. Online ahead of print.
HLA-Bw4 in association with KIR3DL1 favors natural killer cell-mediated protection against severe COVID-19
Ruihua Wang[SUP] 1 [/SUP], Ying Sun[SUP] 1 [/SUP], Bo-Hua Kuang[SUP] 2 [/SUP], Xiao Yan[SUP] 1 3 [/SUP], Jinju Lei[SUP] 4 [/SUP], Yu-Xin Lin[SUP] 1 [/SUP], Jinxiu Tian[SUP] 1 [/SUP], Yating Li[SUP] 1 [/SUP], Xiaoduo Xie[SUP] 3 [/SUP], Tao Chen[SUP] 5 [/SUP], Hui Zhang[SUP] 6 [/SUP], Yi-Xin Zeng[SUP] 1 [/SUP], Jincun Zhao[SUP] 5 [/SUP], Lin Feng[SUP] 1 [/SUP]
Affiliations
Abstract
Replicating SARS-CoV-2 has been shown to degrade HLA class I on target cells to evade the cytotoxic T-cell (CTL) response. HLA-I downregulation can be sensed by NK cells to unleash killer cell immunoglobulin-like receptor (KIR)-mediated self-inhibition by the cognate HLA-I ligands. Here, we investigated the impact of HLA and KIR genotypes and HLA-KIR combinations on COVID-19 outcome. We found that the peptide affinities of HLA alleles were not correlated with COVID-19 severity. The predicted poor binders for SARS-CoV-2 peptides belong to HLA-B subtypes that encode KIR ligands, including Bw4 and C1 (introduced by B*46:01), which have a small F pocket and cannot accommodate SARS-CoV-2 CTL epitopes. However, HLA-Bw4 weak binders were beneficial for COVID-19 outcome, and individuals lacking the HLA-Bw4 motif were at higher risk for serious illness from COVID-19. The presence of the HLA-Bw4 and KIR3DL1 combination had a 58.8% lower risk of developing severe COVID-19 (OR = 0.412, 95% CI = 0.187-0.904, p = 0.02). This suggests that HLA-Bw4 alleles that impair their ability to load SARS-CoV-2 peptides will become targets for NK-mediated destruction. Thus, we proposed that the synergistic responsiveness of CTLs and NK cells can efficiently control SARS-CoV-2 infection and replication, and NK-cell-mediated anti-SARS-CoV-2 immune responses being mostly involved in severe infection when the level of ORF8 is high enough to degrade HLA-I. The HLA-Bw4/KIR3DL1 genotype may be particularly important for East Asians undergoing COVID-19 who are enriched in HLA-Bw4-inhibitory KIR interactions and carry a high frequency of HLA-Bw4 alleles that bind poorly to coronavirus peptides.
Keywords: Bw4 epitope; COVID-19; HLA-KIR interaction; NK cells; SARS-CoV-2.
. 2023 Feb 27;2185467.
doi: 10.1080/22221751.2023.2185467. Online ahead of print.
HLA-Bw4 in association with KIR3DL1 favors natural killer cell-mediated protection against severe COVID-19
Ruihua Wang[SUP] 1 [/SUP], Ying Sun[SUP] 1 [/SUP], Bo-Hua Kuang[SUP] 2 [/SUP], Xiao Yan[SUP] 1 3 [/SUP], Jinju Lei[SUP] 4 [/SUP], Yu-Xin Lin[SUP] 1 [/SUP], Jinxiu Tian[SUP] 1 [/SUP], Yating Li[SUP] 1 [/SUP], Xiaoduo Xie[SUP] 3 [/SUP], Tao Chen[SUP] 5 [/SUP], Hui Zhang[SUP] 6 [/SUP], Yi-Xin Zeng[SUP] 1 [/SUP], Jincun Zhao[SUP] 5 [/SUP], Lin Feng[SUP] 1 [/SUP]
Affiliations
- PMID: 36849422
- DOI: 10.1080/22221751.2023.2185467
Abstract
Replicating SARS-CoV-2 has been shown to degrade HLA class I on target cells to evade the cytotoxic T-cell (CTL) response. HLA-I downregulation can be sensed by NK cells to unleash killer cell immunoglobulin-like receptor (KIR)-mediated self-inhibition by the cognate HLA-I ligands. Here, we investigated the impact of HLA and KIR genotypes and HLA-KIR combinations on COVID-19 outcome. We found that the peptide affinities of HLA alleles were not correlated with COVID-19 severity. The predicted poor binders for SARS-CoV-2 peptides belong to HLA-B subtypes that encode KIR ligands, including Bw4 and C1 (introduced by B*46:01), which have a small F pocket and cannot accommodate SARS-CoV-2 CTL epitopes. However, HLA-Bw4 weak binders were beneficial for COVID-19 outcome, and individuals lacking the HLA-Bw4 motif were at higher risk for serious illness from COVID-19. The presence of the HLA-Bw4 and KIR3DL1 combination had a 58.8% lower risk of developing severe COVID-19 (OR = 0.412, 95% CI = 0.187-0.904, p = 0.02). This suggests that HLA-Bw4 alleles that impair their ability to load SARS-CoV-2 peptides will become targets for NK-mediated destruction. Thus, we proposed that the synergistic responsiveness of CTLs and NK cells can efficiently control SARS-CoV-2 infection and replication, and NK-cell-mediated anti-SARS-CoV-2 immune responses being mostly involved in severe infection when the level of ORF8 is high enough to degrade HLA-I. The HLA-Bw4/KIR3DL1 genotype may be particularly important for East Asians undergoing COVID-19 who are enriched in HLA-Bw4-inhibitory KIR interactions and carry a high frequency of HLA-Bw4 alleles that bind poorly to coronavirus peptides.
Keywords: Bw4 epitope; COVID-19; HLA-KIR interaction; NK cells; SARS-CoV-2.