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

<b>Background:</b> 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. <b>Objective:</b> 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. <b>Results:</b> 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<i>⁣</i> ^<i>∗</i> 003). Conversely, predisposing factors included activator alleles (KIR2DS2, KIR3DS1) and pseudo-alleles (KIR3DP<i>⁣</i> ^<i>∗</i> 001/002). The G ^<i>∗</i> 01:04 allele and G ^<i>∗</i> 01:04-G ^<i>∗</i> 01:04 genotype emerged as protective, while the HLA-E ^<i>∗</i> 01:03-HLA-E ^<i>∗</i> 01:03 genotype may negatively impact disease prognosis. Conversely, the HLA-E ^<i>∗</i> 01:01-HLA-E ^<i>∗</i> 01:03 and HLA-E ^<i>∗</i> 01:01-HLA-E ^<i>∗</i> 01:01 genotypes may confer protection. <b>Conclusion:</b> 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.