Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection
Authors: Littera Roberto , Chessa Luchino , Deidda Silvia , Angioni Goffredo , Campagna Marcello , Lai Sara , Melis Maurizio , Cipri Selene , Firinu Davide , Santus Simonetta , Lai Alberto , Porcella Rita , Rassu Stefania , Meloni Federico , Schirru Daniele , Cordeddu William , Kowalik Marta Anna , Ragatzu Paola , Vacca Monica , Cannas Federica , Alba Francesco , Carta Mauro Giovanni , Del Giacco Stefano , Restivo Angelo , Deidda Simona , Palimodde Antonella , Congera Paola , Perra Roberto , Orrù Germano , Pes Francesco , Loi Martina , Murru Claudia , Urru Enrico , Onali Simona , Coghe Ferdinando , Giglio Sabrina , Perra Andrea 
Published: August 2021

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.