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The polymorphism L412F in TLR3inhibits autophagy and is a marker of severe COVID-19 in males

Authors :
Croci, Susanna
Venneri, Mary Anna
Mantovani, Stefania
Fallerini, Chiara
Benetti, Elisa
Picchiotti, Nicola
Campolo, Federica
Imperatore, Francesco
Palmieri, Maria
Daga, Sergio
Gabbi, Chiara
Montagnani, Francesca
Beligni, Giada
Farias, Ticiana D.J.
Carriero, Miriam Lucia
Di Sarno, Laura
Alaverdian, Diana
Aslaksen, Sigrid
Cubellis, Maria Vittoria
Spiga, Ottavia
Baldassarri, Margherita
Fava, Francesca
Norman, Paul J.
Frullanti, Elisa
Isidori, Andrea M.
Amoroso, Antonio
Mari, Francesca
Furini, Simone
Mondelli, Mario U
study, GEN-COVID multicenter
Chiariello, Mario
Renieri, Alessandra
Meloni, Ilaria
Source :
Autophagy; July 2022, Vol. 18 Issue: 7 p1662-1672, 11p
Publication Year :
2022

Abstract

ABSTRACTThe 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 TLR3L412F-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.Abbreviations: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

Details

Language :
English
ISSN :
15548627 and 15548635
Volume :
18
Issue :
7
Database :
Supplemental Index
Journal :
Autophagy
Publication Type :
Periodical
Accession number :
ejs60379891
Full Text :
https://doi.org/10.1080/15548627.2021.1995152