Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients
Authors: Mantovani Stefania , Daga Sergio , Fallerini Chiara , Baldassarri Margherita , Benetti Elisa , Picchiotti Nicola , Fava Francesca , Gallì Anna , Zibellini Silvia , Bruttini Mirella , Palmieri Maria , Croci Susanna , Amitrano Sara , Alaverdian Diana , Capitani Katia , Furini Simone , Mari Francesca , Meloni Ilaria ,   GEN-COVID Multicenter Study, Montagnani Francesca , Tumbarello Mario , Rancan Ilaria , Fabbiani Massimiliano , Rossetti Barbara , Bergantini Laura , D’Alessandro Miriana , Cameli Paolo , Bennett David , Anedda Federico , Marcantonio Simona , Scolletta Sabino , Franchi Federico , Mazzei Maria Antonietta , Guerrini Susanna , Conticini Edoardo , Cantarini Luca , Frediani Bruno , Tacconi Danilo , Raffaelli Chiara Spertilli , Feri Marco , Donati Alice , Scala Raffaele , Guidelli Luca , Spargi Genni , Corridi Marta , Nencioni Cesira , Croci Leonardo , Caldarelli Gian Piero , Romani Davide , Piacentini Paolo , Bandini Maria , Desanctis Elena , Cappelli Silvia , Canaccini Anna , Verzuri Agnese , Anemoli Valentina , Pisani Manola , Ognibene Agostino , Pancrazzi Alessandro , Lorubbio Maria , Vaghi Massimo , D’Arminio Monforte Antonella , Miraglia Federica Gaia , Bruno Raffaele , Vecchia Marco , Girardis Massimo , Venturelli Sophie , Busani Stefano , Cossarizza Andrea , Antinori Andrea , Vergori Alessandra , Emiliozzi Arianna , Rusconi Stefano , Siano Matteo , Gabrieli Arianna , Riva Agostino , Francisci Daniela , Schiaroli Elisabetta , Paciosi Francesco , Tommasi Andrea , Scotton Pier Giorgio , Andretta Francesca , Panese Sandro , Baratti Stefano , Scaggiante Renzo , Gatti Francesca , Parisi Saverio Giuseppe , Castelli Francesco , Quiros-Roldan Eugenia , Antoni Melania Degli , Zanella Isabella , Della Monica Matteo , Piscopo Carmelo , Capasso Mario , Russo Roberta , Andolfo Immacolata , Iolascon Achille , Fiorentino Giuseppe , Carella Massimo , Castori Marco , Aucella Filippo , Raggi Pamela , Perna Rita , Bassetti Matteo , Di Biagio Antonio , Sanguinetti Maurizio , Masucci Luca , Guarnaccia Alessandra , Valente Serafina , De Vivo Oreste , Doddato Gabriella , Lista Mirjam , Beligni Giada , Valentino Floriana , Zguro Kristina , Tita Rossella , Giliberti Annarita , Mencarelli Maria Antonietta , Rizzo Caterina Lo , Pinto Anna Maria , Ariani Francesca , Di Sarno Laura , Bargagli Elena , Mandalà Marco , Giorli Alessia , Salerni Lorenzo , Zucchi Patrizia , Parravicini Pierpaolo , Menatti Elisabetta , Trotta Tullio , Giannattasio Ferdinando , Coiro Gabriella , Lena Fabio , Lacerenza Gianluca , Mussini Cristina , Martinelli Enrico , Tavecchia Luisa , Belli Mary Ann , Crotti Lia , Parati Gianfranco , Sanarico Maurizio , Raimondi Francesco , Biscarini Filippo , Stella Alessandra , Bachetti Tiziana , La Rovere Maria Teresa , Ludovisi Serena , Bussotti Maurizio , Dei Simona , Ravaglia Sabrina , Artuso Rosangela , Andreucci Elena , Gori Giulia , Pagliazzi Angelica , Fiorentini Erika , Perrella Antonio , Bianchi Francesco , Bergomi Paola , Catena Emanuele , Colombo Riccardo , Luchi Sauro , Morelli Giovanna , Petrocelli Paola , Iacopini Sarah , Modica Sara , Baroni Silvia , Segala Francesco Vladimiro , Falcone Marco , Tiseo Giusy , Barbieri Chiara , Matucci Tommaso , Grassi Davide , Ferri Claudio , Marinangeli Franco , Brancati Francesco , Vincenti Antonella , Borgo Valentina , Lombardi Stefania , Lenzi Mirco , Di Pietro Massimo Antonio , Vichi Francesca , Romanin Benedetta , Attala Letizia , Costa Cecilia , Gabbuti Andrea , Menè Roberto , Colaneri Marta , Casprini Patrizia , Merla Giuseppe , Squeo Gabriella Maria , Maffezzoni Marcello , Frullanti Elisa , Mondelli Mario U. , Renieri Alessandra 
Published: December 2021

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.