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The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.
Susanna Croci; Mary Anna Venneri; Stefania Mantovani; Chiara Fallerini; Elisa Benetti; Nicola Picchiotti; Federica Campolo; Francesco Imperatore; Maria Palmieri; Sergio Daga; Chiara Gabbi; Francesca Montagnani; Giada Beligni; Ticiana D.J. Farias; Miriam L. Carriero; Laura Di Sarno; Diana Alaverdian; Sigrid Aslaksen; Maria Vittoria Cubellis; Ottavia Spiga; Margherita Baldassarri; Francesca Fava; Paul J. Norman; Elisa Frullanti; Andrea M. Isidori; Antonio Amoroso; Francesca Mari; Simone Furini; Mario Mondelli; - GEN-COVID Multicenter Study; Mario Chiariello; Alessandra Renieri; Ilaria Meloni.
Afiliação
  • Susanna Croci; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Mary Anna Venneri; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  • Stefania Mantovani; Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  • Chiara Fallerini; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Elisa Benetti; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Nicola Picchiotti; University of Siena, DIISM-SAILAB, Siena, Italy; Department of Mathematics, University of Pavia, Pavia, Italy
  • Federica Campolo; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  • Francesco Imperatore; Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina, 1 53100 Siena, Italy; Consiglio Nazionale delle Ricerche, Istituto di Fisio
  • Maria Palmieri; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Sergio Daga; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Chiara Gabbi; Independent Medical Scientist, Milan, Italy
  • Francesca Montagnani; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Department of Medical Sciences, Infectious and Tropica
  • Giada Beligni; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Ticiana D.J. Farias; Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aur
  • Miriam L. Carriero; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Laura Di Sarno; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Diana Alaverdian; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Sigrid Aslaksen; Department of Clinical Science, University of Bergen and K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
  • Maria Vittoria Cubellis; Department of Biology, Universita degli Studi di Napoli "Federico II", Napoli, Italy
  • Ottavia Spiga; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena 53100, Italy
  • Margherita Baldassarri; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Francesca Fava; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Paul J. Norman; Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aur
  • Elisa Frullanti; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Andrea M. Isidori; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  • Antonio Amoroso; Department of Medical Sciences, University of Turin, Italy; Immunogenetics and Transplant Biology, Azienda Ospedaliera Universitaria Citta della Salute e della
  • Francesca Mari; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Simone Furini; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
  • Mario Mondelli; Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 1
  • - GEN-COVID Multicenter Study; -
  • Mario Chiariello; Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina, 1 53100 Siena, Italy; Consiglio Nazionale delle Ricerche, Istituto di Fisio
  • Alessandra Renieri; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica
  • Ilaria Meloni; Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21254158
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ABSTRACT
The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired autophagy and reduced TNF production was demonstrated in HEK293 cells transfected with TLR3-L412F plasmid and stimulated with specific agonist poly(IC). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (P=0.038). An increased frequency of autoimmune disorders as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways.
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Texto completo: Disponível Coleções: Preprints Base de dados: medRxiv Tipo de estudo: Cohort_studies / Estudo observacional / Estudo prognóstico Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Preprint
Texto completo
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Texto completo: Disponível Coleções: Preprints Base de dados: medRxiv Tipo de estudo: Cohort_studies / Estudo observacional / Estudo prognóstico Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Preprint