The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants

• Published in: Scientific reports Vol. 13; no. 1; pp. 13078 - 11
• Main Authors: Naushad, Shaik Mohammad, Mandadapu, Gowtham, Ramaiah, Mekala Janaki, Almajhdi, Fahad N., Hussain, Tajamul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114; 631/154; 631/208; 631/250; 631/326; Acetylcysteine; Adaptor Proteins, Signal Transducing - metabolism; Adjuvants, Immunologic; Affinity; Agonists; COVID-19; COVID-19 - genetics; Humanities and Social Sciences; Humans; Male; multidisciplinary; Mutation; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; RNA, Viral; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; TLR7 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-40114-8

We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40–106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (− 328.66 ± 26.03 vs. − 354.08 ± 27.70, p  = 0.03) and MYD88 (β: 40.279, p  = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants ( p  = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC.