IRIS PubliCatt

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 IFN gamma 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 IFN alpha, IFN gamma, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Mantovani, S., Daga, S., Fallerini, C., Baldassarri, M., Benetti, E., Picchiotti, N., Fava, F., Gallì, A., Zibellini, S., Bruttini, M., Palmieri, M., Croci, S., Amitrano, S., Alaverdian, D., Capitani, K., Furini, S., Mari, F., Meloni, I., Francesca Montagnani, 3., 10,, Mario Tumbarello, 3., 10,, Ilaria Rancan, 3., 10,, Massimiliano Fabbiani 10,, Barbara Rossetti 10,, Laura Bergantini 11,, Miriana D’Alessandro 11,, Paolo Cameli 11,, David Bennett 11,, Anedda12, F., Simona Marcantonio 12,, Sabino Scolletta 12,, Federico Franchi 12,, Maria Antonietta Mazzei 13,, Susanna Guerrini 13,, Edoardo Conticini 14,, Luca Cantarini 14,, Bruno Frediani 14,, Danilo Tacconi 15,, Chiara Spertilli Raffaelli15,, Feri16, M., Alice Donati 16,, Scala17, R., Luca Guidelli 17,, Spargi18, G., Marta Corridi 18,, Cesira Nencioni 19,, Leonardo Croci 19,, Gian Piero Caldarelli 20,, Davide Romani 21,, Paolo Piacentini 21,, Maria Bandini 21,, Elena Desanctis 21,, Silvia Cappelli 21,, Anna Canaccini 22,, Agnese Verzuri 22,, Valentina Anemoli 22,, Pisani22, M., Agostino Ognibene 23,, Alessandro Pancrazzi 23,, Maria Lorubbio 23,, Vaghi24, M., Antonella D’Arminio Monforte25,, Federica Gaia Miraglia25,, Raffaele Bruno 26,, 27,, Marco Vecchia 26,, Girardis28, M., Sophie Venturelli 28,, Busani28, S., Andrea Cossarizza 29,, Andrea Antinori 30,, Vergori30, A., Emiliozzi30, A., Stefano Rusconi 31,, 32,, Siano32, M., Arianna Gabrieli 31,, Riva30, A., 31,, Francisci33, D., 34,, Elisabetta Schiaroli 33,, Francesco Paciosi 33,, Tommasi33, A., Pier Giorgio Scotton 35,, Francesca Andretta 35,, Sandro Panese 36,, Stefano Baratti 36,, Renzo Scaggiante 37,, Francesca Gatti 37,, Saverio Giuseppe Parisi 38,, Francesco Castelli 39,, Eugenia Quiros-Roldan 39,, Melania Degli Antoni 39,, Isabella Zanella 40,, 41,, Matteo Della Monica 42,, Carmelo Piscopo 42,, Mario Capasso 43,, 45, 4., Russo43, R., 44,, Andolfo43, I., 44,, Achille Iolascon 43,, 44,, Giuseppe Fiorentino 46,, Massimo Carella 47,, Marco Castori 47,, Aucella48, F., Pamela Raggi 49,, Perna49, R., Matteo Bassetti 50,, 51,, Antonio Di Biagio 50,, 51,, Maurizio Sanguinetti 52,, 53,, Luca Masucci 52,, 53,, Alessandra Guarnaccia 52,, Serafina Valente 54,, Oreste De Vivo54,, Gabriella Doddato, 2., 3,, Mirjam Lista, 2., 3,, Beligni2, G., 3,, Floriana Valentino, 2., 3,, Kristina Zguro, 3., Rossella Tita, 6., Giliberti2, A., 3,, Maria Antonietta Mencarelli, 6., Caterina Lo Rizzo, 6., Anna Maria Pinto6,, Francesca Ariani, 2., 6, 3., Laura Di Sarno2,, 3,, Elena Bargagli 11,, Marco Mandalà 55,, Alessia Giorli 55,, Lorenzo Salerni 55,, Patrizia Zucchi 56,, Parravicini56, P., Elisabetta Menatti 57,, Tullio Trotta 58,, Ferdinando Giannattasio 58,, Coiro58, G., Fabio Lena 59,, Gianluca Lacerenza 59,, Mussini60, C., Enrico Martinelli 61,, Luisa Tavecchia 62,, Mary Ann Belli 62,, Crotti63, L., 65, 6., 67, 6., Gianfranco Parati 63,, 64,, Maurizio Sanarico 68,, Francesco Raimondi 69,, Filippo Biscarini 70,, Alessandra Stella 70,, Tiziana Bachetti 71,, Maria Teresa La Rovere 72,, Ludovisi73, S., Maurizio Bussotti 74,, Dei75, S., Ravaglia76, S., Rosangela Artuso 77,, Elena Andreucci 77,, Gori77, G., Angelica Pagliazzi 77,, Erika Fiorentini 77,, Antonio Perrella 78,, Francesco Bianchi, 3., 78,, Paola Bergomi 79,, Emanuele Catena 79,, Riccardo Colombo 79,, Luchi80, S., Giovanna Morelli 80,, Paola Petrocelli 80,, Sarah Iacopini 80,, Sara Modica 80,, Baroni, S., Francesco Vladimiro Segala 82,, Marco Falcone 83,, Tiseo83, G., Chiara Barbieri 83,, Tommaso Matucci 83,, Davide Grassi 84,, Claudio Ferri 84,, Franco Marinangeli 85,, Francesco Brancati 86,, Antonella Vincenti 87,, Valentina Borgo 87,, Stefania Lombardi 87,, Lenzi87, M., Massimo Antonio Di Pietro 88,, Vichi88, F., Benedetta Romanin 88,, Attala88, L., Cecilia Costa 88,, Gabbuti88, A., Roberto Menè 63,, 64,, Marta Colaneri 26,, Casprini89, P., Giuseppe Merla 43,, 90,, Gabriella Maria Squeo90 And Marcello Maffezzoni 91gen-Covid Multicenter Study,, Frullanti, E., Mondelli, M., Renieri, A., Rare variants in Toll-like receptor 7 results in functional impairmentand downregulation of cytokine-mediated signaling in COVID-19 patients, <<GENES AND IMMUNITY>>, 2022; 23 (1): 51-56. [doi:10.1038/s41435-021-00157-1] [https://hdl.handle.net/10807/234171]

Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients

Mantovani, Susanna;Palmieri, Marco;Baroni, Silvia;
2022

Abstract

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 IFN gamma 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 IFN alpha, IFN gamma, RSAD2, ACOD1, IFIT2, and CXCL10 genes.
2022
Inglese
GENES AND IMMUNITY
Mantovani, S., Daga, S., Fallerini, C., Baldassarri, M., Benetti, E., Picchiotti, N., Fava, F., Gallì, A., Zibellini, S., Bruttini, M., Palmieri, M., Croci, S., Amitrano, S., Alaverdian, D., Capitani, K., Furini, S., Mari, F., Meloni, I., Francesca Montagnani, 3., 10,, Mario Tumbarello, 3., 10,, Ilaria Rancan, 3., 10,, Massimiliano Fabbiani 10,, Barbara Rossetti 10,, Laura Bergantini 11,, Miriana D’Alessandro 11,, Paolo Cameli 11,, David Bennett 11,, Anedda12, F., Simona Marcantonio 12,, Sabino Scolletta 12,, Federico Franchi 12,, Maria Antonietta Mazzei 13,, Susanna Guerrini 13,, Edoardo Conticini 14,, Luca Cantarini 14,, Bruno Frediani 14,, Danilo Tacconi 15,, Chiara Spertilli Raffaelli15,, Feri16, M., Alice Donati 16,, Scala17, R., Luca Guidelli 17,, Spargi18, G., Marta Corridi 18,, Cesira Nencioni 19,, Leonardo Croci 19,, Gian Piero Caldarelli 20,, Davide Romani 21,, Paolo Piacentini 21,, Maria Bandini 21,, Elena Desanctis 21,, Silvia Cappelli 21,, Anna Canaccini 22,, Agnese Verzuri 22,, Valentina Anemoli 22,, Pisani22, M., Agostino Ognibene 23,, Alessandro Pancrazzi 23,, Maria Lorubbio 23,, Vaghi24, M., Antonella D’Arminio Monforte25,, Federica Gaia Miraglia25,, Raffaele Bruno 26,, 27,, Marco Vecchia 26,, Girardis28, M., Sophie Venturelli 28,, Busani28, S., Andrea Cossarizza 29,, Andrea Antinori 30,, Vergori30, A., Emiliozzi30, A., Stefano Rusconi 31,, 32,, Siano32, M., Arianna Gabrieli 31,, Riva30, A., 31,, Francisci33, D., 34,, Elisabetta Schiaroli 33,, Francesco Paciosi 33,, Tommasi33, A., Pier Giorgio Scotton 35,, Francesca Andretta 35,, Sandro Panese 36,, Stefano Baratti 36,, Renzo Scaggiante 37,, Francesca Gatti 37,, Saverio Giuseppe Parisi 38,, Francesco Castelli 39,, Eugenia Quiros-Roldan 39,, Melania Degli Antoni 39,, Isabella Zanella 40,, 41,, Matteo Della Monica 42,, Carmelo Piscopo 42,, Mario Capasso 43,, 45, 4., Russo43, R., 44,, Andolfo43, I., 44,, Achille Iolascon 43,, 44,, Giuseppe Fiorentino 46,, Massimo Carella 47,, Marco Castori 47,, Aucella48, F., Pamela Raggi 49,, Perna49, R., Matteo Bassetti 50,, 51,, Antonio Di Biagio 50,, 51,, Maurizio Sanguinetti 52,, 53,, Luca Masucci 52,, 53,, Alessandra Guarnaccia 52,, Serafina Valente 54,, Oreste De Vivo54,, Gabriella Doddato, 2., 3,, Mirjam Lista, 2., 3,, Beligni2, G., 3,, Floriana Valentino, 2., 3,, Kristina Zguro, 3., Rossella Tita, 6., Giliberti2, A., 3,, Maria Antonietta Mencarelli, 6., Caterina Lo Rizzo, 6., Anna Maria Pinto6,, Francesca Ariani, 2., 6, 3., Laura Di Sarno2,, 3,, Elena Bargagli 11,, Marco Mandalà 55,, Alessia Giorli 55,, Lorenzo Salerni 55,, Patrizia Zucchi 56,, Parravicini56, P., Elisabetta Menatti 57,, Tullio Trotta 58,, Ferdinando Giannattasio 58,, Coiro58, G., Fabio Lena 59,, Gianluca Lacerenza 59,, Mussini60, C., Enrico Martinelli 61,, Luisa Tavecchia 62,, Mary Ann Belli 62,, Crotti63, L., 65, 6., 67, 6., Gianfranco Parati 63,, 64,, Maurizio Sanarico 68,, Francesco Raimondi 69,, Filippo Biscarini 70,, Alessandra Stella 70,, Tiziana Bachetti 71,, Maria Teresa La Rovere 72,, Ludovisi73, S., Maurizio Bussotti 74,, Dei75, S., Ravaglia76, S., Rosangela Artuso 77,, Elena Andreucci 77,, Gori77, G., Angelica Pagliazzi 77,, Erika Fiorentini 77,, Antonio Perrella 78,, Francesco Bianchi, 3., 78,, Paola Bergomi 79,, Emanuele Catena 79,, Riccardo Colombo 79,, Luchi80, S., Giovanna Morelli 80,, Paola Petrocelli 80,, Sarah Iacopini 80,, Sara Modica 80,, Baroni, S., Francesco Vladimiro Segala 82,, Marco Falcone 83,, Tiseo83, G., Chiara Barbieri 83,, Tommaso Matucci 83,, Davide Grassi 84,, Claudio Ferri 84,, Franco Marinangeli 85,, Francesco Brancati 86,, Antonella Vincenti 87,, Valentina Borgo 87,, Stefania Lombardi 87,, Lenzi87, M., Massimo Antonio Di Pietro 88,, Vichi88, F., Benedetta Romanin 88,, Attala88, L., Cecilia Costa 88,, Gabbuti88, A., Roberto Menè 63,, 64,, Marta Colaneri 26,, Casprini89, P., Giuseppe Merla 43,, 90,, Gabriella Maria Squeo90 And Marcello Maffezzoni 91gen-Covid Multicenter Study,, Frullanti, E., Mondelli, M., Renieri, A., Rare variants in Toll-like receptor 7 results in functional impairmentand downregulation of cytokine-mediated signaling in COVID-19 patients, <<GENES AND IMMUNITY>>, 2022; 23 (1): 51-56. [doi:10.1038/s41435-021-00157-1] [https://hdl.handle.net/10807/234171]
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