The polymorphism L412F in inhibits autophagy and is a marker of severe COVID-19 in males.

Diana Alaverdian, Ilaria Meloni, Alessandra Renieri, Mario Chiariello, Mario U Mondelli, Simone Furini, Francesca Mari, Antonio Amoroso, Andrea M Isidori, Elisa Frullanti, Paul J Norman, Francesca Fava, Margherita Baldassarri, Ottavia Spiga, Maria Vittoria Cubellis, Sigrid Aslaksen, Susanna Croci, Laura Di Sarno, Miriam Lucia Carriero, Ticiana D J Farias, Giada Beligni, Francesca Montagnani, Chiara Gabbi, Sergio Daga, Maria Palmieri, Francesco Imperatore, Federica Campolo, Nicola Picchiotti, Elisa Benetti, Chiara Fallerini, Stefania Mantovani, Mary Anna Venneri

Journal: Autophagy 2022;18(7):1662-1672

PMID: 34964709

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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 macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3-encoding plasmid and stimulated with specific agonist poly(I:C). 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 such 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. AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor.

Address: Medical Genetics, University of Siena, Siena, Italy.; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.; Division of Clinical Immunology and Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.; DIISM-SAILAB, University of Siena, Siena, Italy.; Department of Mathematics, University of Pavia, Pavia, Italy.; Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Core Research Laboratory, Via Fiorentina, Siena, Italy.; Consiglio Nazionale delle Ricerche, Istituto DI Fisiologia Clinica, Siena, Italy.; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; Department of Medical Sciences, Infectious and Tropical Diseases Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy.; Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Department of Clinical Science, Universty of Bergen and K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.; Department of Biology, Università Degli Studi di Napoli "Federico II", Napoli, Italy.; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.; Department of Medical Sciences, University of Turin, Turin, Italy.; Immunogenetics and Transplant Biology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Italy.; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy.; Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

DOI: 10.1080/15548627.2021.1995152

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https://medlineplus.gov/covid19coronavirusdisease2...

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https://figshare.com/articles/by-resource-doi/10.1...

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https://assays.cancer.gov/CPTAC-438

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https://antibodies.cancer.gov/detail/CPTC-HLA-DQA1...

MeSH Terms: Autophagy, Biomarkers, COVID-19, HEK293 Cells, Humans, Hydroxychloroquine, Male, Polymorphism, Single Nucleotide, SARS-CoV-2, Severity of Illness Index, Toll-Like Receptor 3