IFNAR2 p.F8S Variant Associates with Severe COVID-19 and Adaptive Immune Cell Activation Modulation
Year: 2026
Type: article
Study design: Observational Study
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a wide range of clinical manifestations modulated by genetic factors. The aim of this study was to identify genetic determinants of severe COVID-19 affecting protein sequence to gain insight into disease pathogenesis. Variants prioritized in two patients requiring lung transplant were tested in the Milan FOGS cohort (487/869 cases/controls), highlighting an independent association between the p.F8S low-frequency variant of interferon alpha receptor 2 gene (IFNAR2) and severe disease (OR = 1.73 [1.24–2.42], p = 0.001), replicated in the COVID-19 Host Genetics Initiative cohort (26,167/2,061,934 cases/controls). In the FOGS cohort, the p.F8S variant was linked to higher circulating IL-6 levels. In keeping, bulk transcriptomic analysis in PBMCs at the peak of infection (n = 57) showed that carriers of the p.F8S variant had upregulation of immune signaling and pathogens response (p < 0.05). Functional flow cytometry experiments in healthy donors (n = 12) revealed that membrane IFNAR2 protein expression was reduced in B lymphocytes, but higher in dendritic cells (p < 0.05). Finally, by interrogating a public scRNAseq resource of PBMC of people with COVID-19, we showed that p.F8S carriers had upregulation of immune pathways specifically in dendritic cells (p < 0.05). These results suggest that the p.F8S variant may influence COVID-19 severity by enhancing adaptive immune response, thereby favoring inflammation.
DOI: 10.3390/ijms27020992
Authors: Francesco Malvestiti, Angela Lombardi, Francesco Gentile, Veronica Torcianti, Elena Trombetta, Alessandro Cherubini, Giuseppe Lamorte, Sara Uceda Renteria, Daniele Marchelli, Lorenzo Rosso, Alessandra Bandera, Flora Peyvandi, Francesco Blasi, Giacomo Grasselli, Laura Porretti, Saleh Alqahtani, Daniele Prati, Roberta Gualtierotti, Blagoje Soskic, Valentina Vaira, Luisa Ronzoni, Luca Valenti
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funder: European Commission
OpenAlex ID: W7125008521