Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection

Abstract

Background The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study’s focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. Methods KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. Results Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1–2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3–0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3–0.7), PM = 0.0005, PMC = 0.005]. Conclusions The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.

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

“…This expansion was also found in convalescent individuals two months post-infection, although with less difference compared to infection-naïve individuals. The overexpression of inhibitory 2DL1 in CD56 dim CD16 neg and CD56 dim CD16 pos NK cell subsets was found by Littera et al, who described a higher frequency of the KIR2DL1 and 2DL3 inhibitory KIR gene profile in individuals infected with SARS-CoV-2, suggesting that they are more susceptible to contracting this viral infection, in line with our study [35]. Unfortunately, this study did not differentiate among different NK cell subsets.…”

“…Finally, CD56 dim CD16 neg NK cells are unconventional CD56 dim cells whose cytotoxic capacity has been found to be lower compared to that of CD56 dim CD16 pos NK cells [32,33]. In this regard, the downregulation of CD16 expression has been also described in Herpes and Varicella zoster infections and might be associated with abnormal NK cell maturation during infection or prolonged cellular activity/activation, driving CD16 shedding, which might be a regulatory mechanism to prevent activation-induced cell death [34][35][36][37]. CD56 dim CD16 neg NK cells are considered to be the precursors of CD56 dim CD16 pos NK cells.…”

The New Kid on the Block: HLA-C, a Key Regulator of Natural Killer Cells in Viral Immunity

“…HLA-C*05:01-restricted peptides promote binding and activation of KIR2DS4 + NK cells [194]. The gene combination of KIR2DS2/HLA-C1 was more common in asymptomatic-paucisymptomatic patients compared to patients with severe symptoms [195].…”

A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome

“…In addition to responsiveness to sHLH therapies, there are mounting reports of genetic influence on COVID-19 severity, allowing for possible prediction of disease course and early intervention. Differences in haplotypes of killer-cell immune-globulin-like receptors (KIRs) has been shown to be informative of disease course, with the KIR2DS2/HLA C1 function unit protective against COVID-19 adverse outcomes [25]. Conversely, heterozygous mutations, largely missense, in pHLH genes have been correlated with severe COVID-19 symptomology and clinical outcomes [6].…”