Enrique Bernal1, Lourdes Gimeno2,3, María J Alcaraz1, Ahmed A Quadeer4, Marta Moreno5, María V Martínez-Sánchez2, José A Campillo2, Jose M Gomez5, Ana Pelaez6, Elisa García7, Maite Herranz5, Marta Hernández-Olivo8, Elisa Martínez-Alfaro9, Antonia Alcaraz1, Ángeles Muñoz1, Alfredo Cano1, Matthew R McKay4,10, Manuel Muro2, Alfredo Minguela2. 1. Infectious Disease Unit, Reina Sofia University Hospital and the Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain. 2. Immunology Service, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain. 3. Human Anatomy Department, University of Murcia, Murcia, Spain. 4. Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China. 5. Internal Medicine Service, Hospital Universitario Morales Meseguer, Murcia, Spain. 6. Internal Medicine Service, Hospital Rafael Méndez, Lorca, Spain. 7. Infectious Disesase Unit, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain. 8. Pheumology Service, Hospital Universitario Santa Lucía, Murcia, Spain. 9. Internal Medicine Service, Hospital General de Albacete, Albacete, Spain. 10. Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
Abstract
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.
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.
Authors: Maria Karoliny da Silva Torres; Carlos David Araújo Bichara; Maria de Nazaré do Socorro de Almeida; Mariana Cayres Vallinoto; Maria Alice Freitas Queiroz; Izaura Maria Vieira Cayres Vallinoto; Eduardo José Melo Dos Santos; Carlos Alberto Marques de Carvalho; Antonio Carlos R Vallinoto Journal: Front Microbiol Date: 2022-02-10 Impact factor: 5.640
Authors: Juan Francisco Gutiérrez-Bautista; Alba Martinez-Chamorro; Antonio Rodriguez-Nicolas; Antonio Rosales-Castillo; Pilar Jiménez; Per Anderson; Miguel Ángel López-Ruz; Miguel Ángel López-Nevot; Francisco Ruiz-Cabello Journal: Int J Mol Sci Date: 2022-06-23 Impact factor: 6.208