Activating Killer-cell Immunoglobulin-like Receptors are associated with the severity of COVID-19

Bernal, Enrique; Gimeno, Lourdes; Alcaraz, María J; Quadeer, Ahmed A; Moreno, Marta; Martínez-Sánchez, María V; Campillo, José A; Gomez, Jose M; Pelaez, Ana; García, Elisa; Herranz, Maite; Hernández-Olivo, Marta; Martínez-Alfaro, Elisa; Alcaraz, Antonia; Muñoz, Ángeles; Cano, Alfredo; McKay, Matthew R; Muro, Manuel; Minguela, Alfredo

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.