tetano
Editor, Senior Moderator
Autophagy
. 2021 Dec 29;1-11.
doi: 10.1080/15548627.2021.1995152. Online ahead of print.
The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males
Susanna Croci[SUP] 1 2 [/SUP], Mary Anna Venneri[SUP] 3 [/SUP], Stefania Mantovani[SUP] 4 [/SUP], Chiara Fallerini[SUP] 1 2 [/SUP], Elisa Benetti[SUP] 2 [/SUP], Nicola Picchiotti[SUP] 5 6 [/SUP], Federica Campolo[SUP] 3 [/SUP], Francesco Imperatore[SUP] 7 8 [/SUP], Maria Palmieri[SUP] 1 2 [/SUP], Sergio Daga[SUP] 1 2 [/SUP], Chiara Gabbi[SUP] 9 [/SUP], Francesca Montagnani[SUP] 2 10 [/SUP], Giada Beligni[SUP] 1 2 [/SUP], Ticiana D J Farias[SUP] 11 [/SUP], Miriam Lucia Carriero[SUP] 1 2 [/SUP], Laura Di Sarno[SUP] 1 2 [/SUP], Diana Alaverdian[SUP] 1 2 [/SUP], Sigrid Aslaksen[SUP] 12 [/SUP], Maria Vittoria Cubellis[SUP] 13 [/SUP], Ottavia Spiga[SUP] 14 [/SUP], Margherita Baldassarri[SUP] 1 2 [/SUP], Francesca Fava[SUP] 1 2 [/SUP], Paul J Norman[SUP] 11 [/SUP], Elisa Frullanti[SUP] 1 2 [/SUP], Andrea M Isidori[SUP] 3 [/SUP], Antonio Amoroso[SUP] 15 16 [/SUP], Francesca Mari[SUP] 1 2 17 [/SUP], Simone Furini[SUP] 2 [/SUP], Mario U Mondelli[SUP] 4 18 [/SUP], Gen-Covid Multicenter Study[SUP] 1 [/SUP], Mario Chiariello[SUP] 7 8 [/SUP], Alessandra Renieri[SUP] 1 2 17 [/SUP], Ilaria Meloni[SUP] 1 2 [/SUP]
Affiliations
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[SUP]L412F[/SUP]-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.
Keywords: Autophagy; COVID-19; HLA; L412F; TLR3.
. 2021 Dec 29;1-11.
doi: 10.1080/15548627.2021.1995152. Online ahead of print.
The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males
Susanna Croci[SUP] 1 2 [/SUP], Mary Anna Venneri[SUP] 3 [/SUP], Stefania Mantovani[SUP] 4 [/SUP], Chiara Fallerini[SUP] 1 2 [/SUP], Elisa Benetti[SUP] 2 [/SUP], Nicola Picchiotti[SUP] 5 6 [/SUP], Federica Campolo[SUP] 3 [/SUP], Francesco Imperatore[SUP] 7 8 [/SUP], Maria Palmieri[SUP] 1 2 [/SUP], Sergio Daga[SUP] 1 2 [/SUP], Chiara Gabbi[SUP] 9 [/SUP], Francesca Montagnani[SUP] 2 10 [/SUP], Giada Beligni[SUP] 1 2 [/SUP], Ticiana D J Farias[SUP] 11 [/SUP], Miriam Lucia Carriero[SUP] 1 2 [/SUP], Laura Di Sarno[SUP] 1 2 [/SUP], Diana Alaverdian[SUP] 1 2 [/SUP], Sigrid Aslaksen[SUP] 12 [/SUP], Maria Vittoria Cubellis[SUP] 13 [/SUP], Ottavia Spiga[SUP] 14 [/SUP], Margherita Baldassarri[SUP] 1 2 [/SUP], Francesca Fava[SUP] 1 2 [/SUP], Paul J Norman[SUP] 11 [/SUP], Elisa Frullanti[SUP] 1 2 [/SUP], Andrea M Isidori[SUP] 3 [/SUP], Antonio Amoroso[SUP] 15 16 [/SUP], Francesca Mari[SUP] 1 2 17 [/SUP], Simone Furini[SUP] 2 [/SUP], Mario U Mondelli[SUP] 4 18 [/SUP], Gen-Covid Multicenter Study[SUP] 1 [/SUP], Mario Chiariello[SUP] 7 8 [/SUP], Alessandra Renieri[SUP] 1 2 17 [/SUP], Ilaria Meloni[SUP] 1 2 [/SUP]
Affiliations
- PMID: 34964709
- DOI: 10.1080/15548627.2021.1995152
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[SUP]L412F[/SUP]-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.
Keywords: Autophagy; COVID-19; HLA; L412F; TLR3.