# 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

## TL;DR

This study explores how genetic variations in immune-related genes affect the severity of COVID-19, showing that certain gene variants can protect against or worsen the disease.

## Contribution

The study identifies specific KIR, HLA-E, and HLA-G alleles associated with mild or severe outcomes in SARS-CoV-2 infection.

## Key findings

- Inhibitory KIR alleles like KIR2DL1 and KIR3DL1 are linked to protection against severe disease.
- Activator alleles such as KIR2DS2 and KIR3DS1 are associated with increased disease severity.
- HLA-E genotypes like HLA-E∗01:01-HLA-E∗01:03 may offer protection, while HLA-E∗01:03-HLA-E∗01:03 may worsen prognosis.

## 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.