Activating Killer-Cell Immunoglobulin-Like Receptors Are Associated With the Severity of Coronavirus Disease 2019

Abstract

Background Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. Here 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 KIR and HLA-I genotyping and NK cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 non-infected controls. Results NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4 low CD16 low CD226 low CD56 high TIGIT high NKG2A high), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe than mild/moderate patients and controls (83.7%, 55.7% and 36.2%, p<7.7x10 -9). In mild/moderate patients HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared to patients with other HLA-B*15 subtypes and non-infected controls (90.9%, 42.9% and 47.3%, p<0.002, Pc=0.022). This strongly suggests that HLA-B*15:01 specifically presenting SARS-CoV-2 peptides could form a neo-ligand interacting with KIR3DS1. Similarly, a putative neo-ligand for KIR2DS4 could arise from other HLA-I molecules presenting SARS-CoV-2 peptides expressed on infected/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 to disease severity.

Immunopathology and Immunosenescence, the Immunological Key Words of Severe COVID-19. Is There a Role for Stem Cell Transplantation?

“…Additionally, NK cell cytotoxic and secretory functions are tightly regulated by a dynamic balance between activating and inhibitory signals from an arsenal of membrane receptors, including killer cell immunoglobulin-like receptors (KIRs), randomly generated during NK cell differentiation and maturation ( Vidal et al, 2011 ). Specific KIR/ligand interactions seem to be associated with COVID-19 disease severity as demonstrated in a very recent paper ( Bernal et al, 2021 ) and by preliminary results from our ongoing study (unpublished observations).…”

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

“…Our study showed a direct correlation of the activating 2DS4 receptor with the plasma level of IFN-γ and IL6 in COVID-19 patients, biomarkers that are reported to be elevated during SARS-CoV-2 infection [25] in accordance with our study, although the production of these cytokines is systemic and can be partially attributed to the NK cell production. One recent study reported that the frequency of the 2DS4 gene was significantly increased in COVID-19 patients compared to controls [26].…”

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

“…Only five studies have investigated the impact of KIR receptors on SARS-CoV-2 infection ( Beksac et al, 2021 ; Bernal et al, 2021 ; Lesan et al, 2021 ; Littera et al, 2021 ; Hajeer et al, 2022 ). In contrast to our findings, a study with a small number of 16 patients from the German Caucasian cohort revealed that patients with activating KIR2DS5 were recovered from COVID-19 in a shorter time than the individuals negative for the KIR2DS5 gene ( Lesan et al, 2021 ).…”

“…However, this study did not determine the frequencies of specific KIR and cognate HLA class I ligand combinations. Higher frequencies for KIR2DS4 in severe COVID-19 patients and KIR3DS1 + HLA-B*15:01 + in mild/moderate cases of COVID-19 than in control in Spanish indicate a potentially detrimental effect of activating KIR in COVID-19 ( Bernal et al, 2021 ). However, none of these genes and combinations were found to be significant in our study, probably because of the limited sample sizes in these other studies.…”