The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

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 L412F -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

Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe

“…Candidate negatively selected variants included the hypomorphic LBP D283G and TB-risk TYK2 P1104A variants, together with TLR3 L412F, which is associated with mild protection against autoimmune thyroid disease (OR = 0.93; p = 7.0 x 10 -12 ) 80 but with a modest increase in the risk of severe COVID-19 pneumonia, 81 and IL23R R381Q, which increases IBD risk (OR = 1.93) 82 . Autosomal recessive or dominant TLR3 deficiency underlies viral diseases of the brain and lungs, 83,84 whereas autosomal recessive IL23R deficiency underlies clinical disease caused by weakly virulent fungi and mycobacteria.…”

Induction of Innate Immune Response by TLR3 Agonist Protects Mice against SARS-CoV-2 Infection

“…The central role of PRRs in coping with COVID-19 has been recently suggested. For example, inborn genetic polymorphisms in TLR3-dependent IFN I signaling pathways were associated with COVID-19 life-threatening pneumonia [45]. Another study argued that the low percentage of COVID-19-hospitalized patients under the age of 18 is correlated with higher expression of MDA5 in their nasal turbinates compared to adults, resulting in an immediate response to infection [46].…”

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19

“…Thus, TLR-3 deficiency is associated with high susceptibility to RNA virus infection, and the deficiency or mutation of the rs3775291 polymorphism prevents its expression and is also associated with diabetes and pulmonary hypertension. This leads to a rapid progression of COVID-19 in infected patients [15,184].…”