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Published on: February 28, 2021
Activating Killer-Cell Immunoglobulin-Like Receptors Are Associated With the Severity of Coronavirus Disease 2019
Enrique Bernal1, Lourdes Gimeno2,3, María J Alcaraz1
1Infectious Disease Unit, Reina Sofia University Hospital and the Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
Insights
Killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions influence COVID-19 severity. Specific KIR/HLA-I interactions are linked to natural killer cell activation and disease outcomes in COVID-19 patients.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- The reasons for varying clinical outcomes in COVID-19 patients are not fully understood.
- Investigating genetic factors like killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen class-I (HLA-I) interactions may explain COVID-19's clinical variability.
Purpose of the Study:
- To explore the association between KIR/HLA-I interactions and COVID-19 susceptibility and severity.
- To identify specific genetic markers that correlate with different COVID-19 disease courses.
Main Methods:
- Genotyping for KIR and HLA-I was performed on 201 symptomatic COVID-19 patients and 210 healthy controls.
- Immunophenotyping of natural killer cell (NKc) receptors was conducted to analyze NKc activation status.
Main Results:
- Severe COVID-19 cases showed an expansion of activated NKcs (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh).
- Higher frequencies of the activating KIR2DS4 gene were observed in severe COVID-19 patients compared to mild/moderate cases and controls.
- The HLA-B*15:01 allele was linked to increased frequencies of the activating KIR3DS1 gene in mild/moderate COVID-19 patients, suggesting a potential neoligand interaction with SARS-CoV-2 peptides.
Conclusions:
- Natural killer cells play a significant role in the diverse clinical manifestations of COVID-19.
- Specific KIR/HLA-I interactions are strongly associated with COVID-19 disease severity, potentially through novel ligand formations.
Background:
Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19.
Methods:
We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls.
Results:
The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, P < 7.7 × 10-9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; P < .002; Pc = 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells.
Conclusions:
Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.
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