HLA-Bw4 in association with KIR3DL1 favors natural killer cell-mediated protection against severe COVID-19. Issue 1 (31st December 2023)

• Record Type: Journal Article
• Authors: Wang, Ruihua; Sun, Ying; Kuang, Bo-Hua; Yan, Xiao; Lei, Jinju; Lin, Yu-Xin; Tian, Jinxiu; Li, Yating; Xie, Xiaoduo; Chen, Tao; Zhang, Hui; Zeng, Yi-Xin; Zhao, Jincun; Feng, Lin
• Is Part Of: Emerging microbes & infections. Volume 12:Issue 1(2023)
• Publication Date: 2023-12-31
• Subjects: COVID-19 -- SARS-CoV-2 -- NK cells -- Bw4 epitope -- HLA-KIR interaction; Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1080/22221751.2023.2185467
• Languages: English
• ISSNs: 2222-1751

Abstract

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.