Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males

Fallerini, C.; Daga, S.; Mantovani, S.; Benetti, E.; Pujol, A.; Picchiotti, N.; Schluter, A.; Planas-Serra, L.; Troya, J.; Baldassarri, M.; Fava, F.; Ludovisi, S.; Castelli, F.; Quiros-Roldan, M. E.; Vaghi, M.; Rusconi, S.; Siano, M.; Bandini, M.; Furini, S.; Mari, F.; GEN-COVID Multicenter Study,; Renieri, A.; Mondelli, M. U.; Frullanti, E.

Background: COVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7. Objective: We sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: We compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on the young male subset, picking up TLR7 as the most important susceptibility gene. Results: Rare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-[a] and IFN-{gamma} in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses. Conclusion: Young males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.