Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity
Mattia Laffranchi,
Elvezia Maria Paraboschi,
Francisco Bianchetto-Aguilera,
Nicola Tamassia,
Sara Gasperini,
Elisa Gardiman,
Arianna Piserà,
Annalisa Del Prete,
Pietro Invernizzi,
Angela Gismondi,
Alberto Mantovani,
Marco A. Cassatella,
Rosanna Asselta,
Silvano Sozzani
Affiliations
Mattia Laffranchi
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy; Corresponding author. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Elvezia Maria Paraboschi
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Francisco Bianchetto-Aguilera
Department of Medicine, Section of General Pathology, University of Verona, 37134, Verona, Italy
Nicola Tamassia
Department of Medicine, Section of General Pathology, University of Verona, 37134, Verona, Italy
Sara Gasperini
Department of Medicine, Section of General Pathology, University of Verona, 37134, Verona, Italy
Elisa Gardiman
Department of Medicine, Section of General Pathology, University of Verona, 37134, Verona, Italy
Arianna Piserà
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Annalisa Del Prete
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Pietro Invernizzi
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo Dei Tintori, Monza, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Angela Gismondi
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
Alberto Mantovani
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
Marco A. Cassatella
Department of Medicine, Section of General Pathology, University of Verona, 37134, Verona, Italy
Rosanna Asselta
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Corresponding author. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
Silvano Sozzani
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
The 3p21.31 locus is the most robust genomic region associated with COVID-19 severity. This locus contains a main chemokine receptor (CKR) cluster. We tested expression quantitative trait loci (eQTL) targeting the 3p21.31 CKR cluster linked to COVID-19 hospitalization in Europeans from the COVID-19 HGI meta-analysis. Among these, CCRL2, a key regulator of neutrophil trafficking, was targeted by neutrophil-restricted eQTLs. We confirmed these eQTLs in an Italian COVID-19 cohort. Haplotype analysis revealed a link between an increased CCRL2 expression and COVID-19 severity and hospitalization. By the exposure of neutrophils to a TLR8 ligand, reflecting a viral infection, we revealed specific chromatin domains within the 3p21.31 locus exclusive to neutrophils. In addition, the identified variants mapped within these regions altered the binding motif of neutrophils-expressed transcription factors. These results support that CCRL2 eQTL variants contribute to the risk of severe COVID-19 by selectively affecting neutrophil functions.
