Mechanistic insights into TLR7-mediated clinical outcome in COVID-19 and the potential modulatory role of N-acetylcysteine

Abstract Men with loss-of-function (LOF) variants of toll-like receptor 7 (TLR7) are more susceptible to critical COVID-19. We aimed to determine the pathogenicity and binding affinity changes of TLR7 variants towards SARS-CoV2 RNA, MyD88, imiquimod, and N-acetylcysteine (NAC). TLR7 deleterious mutations increase the risk of critical COVID-19 by 16-folds (95% CI: 2.40–106.73, p = 0.005). LOF-TLR7 variants had impaired SARS COV-2 viral RNA sensing (-292.09 ± 11.86 Kcal/mol) compared to hypofunctional (-304.65 +/- 8.84 Kcal/mol), and neutral (-310.01 ± 5.29 Kcal/mol) TLR7 variants (p < 0.00001). The hypofunctional TLR7 variants had the lowest binding affinity (-270.31 ± 8.35 Kcal/mol) to MyD88, while the LOF variants had the highest binding affinity (-284.87 ± 13.20 Kcal/mol, F:4.66, p = 0.02). The TLR7 variants in critical COVID-19 had a higher binding affinity to N-acetylcysteine (NAC) than those in severe COVID-19 (-7.68 ± 0.68 vs.-7.18 ± 0.35, p = 0.03). The binding affinity of imiquimod to TLR7 variants is not altered by the TLR7 functionality (F = 1.09, p = 0.36). To conclude, men with deleterious TLR7 mutations are highly prone to critical COVID-19 due to loss of viral RNA sensing ability of TLR7, which impairs anti-viral response. NAC can circumvent the impact of these TLR gene variants and elicit anti-viral responses by relaying TLR7-MyD88 signaling while imiquimod was not effective.