The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.
The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.
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TLR3中L412F多态性抑制自噬，是男性严重COVID-19的标志。
DOI：
10.1080/15548627.2021.1995152
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发表时间：
2022-07
期刊：
影响因子：
13.3
通讯作者：
Meloni, Ilaria
中科院分区：
文献类型：
--
作者：
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.;Chiariello, Mario;Renieri, Alessandra;Meloni, Ilaria
TLR 3基因L412 F多态性与多种感染性疾病相关。然而，这种关联的机制仍然是未知的。在这里，我们表明TLR 3中的L412 F多态性是COVID-19严重程度的标志。这种关联在男性子队列中增加。在用TLR 3L 412 F编码质粒转染并用特异性激动剂poly（I：C）刺激的HEK 293细胞中证明了大自噬/自噬受损和TNF/TNFα产生减少。在接受自噬抑制剂羟氯喹治疗的L412 F COVID-19患者中，28天的生存率在统计学上显著降低（p = 0.038）。在L412 F COVID-19男性中发现自身免疫性疾病（如共病）的频率增加，这些男性具有易于自身抗原呈递的特定II类HLA单倍型。我们的分析表明，L412 F多态性使男性面临严重COVID-19的风险，并为重新解释考虑自噬途径的临床试验提供了理论基础。缩略语：美联社：自噬体;曲线下面积：曲线下面积; BafA1：巴弗洛霉素A1; COVID-19：冠状病毒病-2019; HCQ：羟氯喹; RAP：雷帕霉素; ROC：受试者操作特征; SARS-CoV-2：严重急性呼吸综合征冠状病毒2型; TLR：Toll样受体; TNF/TNF-α：肿瘤坏死因子
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 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
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