The Impact of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen-E, Human Leukocyte Antigen-G Polymorphisms on Innate Immunity and COVID-19 Severity

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection spans a spectrum of symptoms, ranging from mild respiratory issues to severe outcomes like pneumonia, acute respiratory distress syndrome, and fatality. Natural killer (NK) cells, governed by killer cell immunoglobulin-like receptors (KIRs), play a pivotal role in directly combating viral infections. Emerging studies indicate a decline in NK cell numbers and heightened NKG2A expression in infected individuals. Objective: This study focuses on genotyping human leukocyte antigen (HLA)-E, HLA-G, and KIR in SARS-CoV-2-positive individuals, comparing data between those with mild and moderate/severe symptoms. The cohort comprised 100 COVID-19-positive patients and 100 healthy volunteers, both groups subjected to DNA isolation and genotyping using sequence-based sequencing. Results: In 97 COVID-19-positive patients (52 mild, 24 moderate, and 21 severe) and 100 healthy volunteers, the study revealed protective associations with inhibitory alleles (KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, and pseudo-alleles like KIR3DP1⁣ ^∗ 003). Conversely, predisposing factors included activator alleles (KIR2DS2, KIR3DS1) and pseudo-alleles (KIR3DP⁣ ^∗ 001/002). The G ^∗ 01:04 allele and G ^∗ 01:04-G ^∗ 01:04 genotype emerged as protective, while the HLA-E ^∗ 01:03-HLA-E ^∗ 01:03 genotype may negatively impact disease prognosis. Conversely, the HLA-E ^∗ 01:01-HLA-E ^∗ 01:03 and HLA-E ^∗ 01:01-HLA-E ^∗ 01:01 genotypes may confer protection. Conclusion: Genetic variations in KIR, HLA-E, and HLA-G are associated with susceptibility and resistance to severe COVID-19 outcomes. This elucidates the intricate interplay of NK cells and immune-related genes, offering insights into potential therapeutic avenues and personalized approaches.

Keywords: COVID-19; HLA-G genotype; Human Leukocyte Antigen-E (HLA-E); killer cell immunoglobulin-like receptor (KIR); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Figure 1

KIR allele frequencies in control and patient groups. The figure illustrates the frequencies of KIR in control and patient groups. The data were processed and visualized by the authors using R programing. The bars represent the percentage frequencies of different KIR receptors observed in both control and patient groups. KIR, killer cell immunoglobulin-like receptor.

Figure 2

HLA allele frequencies in control and patient groups. The bars represent the frequencies of different alleles observed in both control and patient groups. (All components of this figure were generated by the authors using R programing unless otherwise stated). HLA, human leukocyte antigen.