The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.
Autophagy
; 18(7): 1662-1672, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-34964709
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 TLR3L412F-encoding 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 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
4_TD
Problema de saúde:
4_pneumonia
Assunto principal:
Receptor 3 Toll-Like
/
COVID-19
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Autophagy
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália