Antolí, ArnauVargas Parra, Gardenía MaríaSierra Fortuny, ÀngelsGómez Vázquez, José LuisRofes, PaulaMunté, ElisabetViana Errasti, JulenMarín Montes, RaúlLópez Dóriga Guerra, AdrianaFeliubadaló, LidiaValle, Jesús delPérez González, AlexandrePoveda, EvaSolanich, XavierLázaro García, Conxi2025-07-152025-07-152025-05-271573-2592https://hdl.handle.net/2445/222239TLR7, which encodes a key receptor for single-stranded RNA (ssRNA) virus of the innate immune system, was recently associated with X-linked immunodeficiency and COVID-19 susceptibility. This study investigates the association between TLR7 variants and susceptibility to severe COVID-19 in a multicentric Spanish cohort. The TLR7 gene was sequenced in a cohort of 365 COVID-19 patients, stratified into two groups: one comprising mild and asymptomatic patients, considered as controls (n = 87), and the other consisting of moderate to severely affected patients hospitalized due to COVID-19 pneumonia, considered as cases (n = 278). A total of 152 unique TLR7 variants were identified, of note, six rare variants were identified in 11 cases (3.96%), all of whom belonged to the case group. The functional impact of rare TLR7 variants was assessed using a luciferase reporter assay and revealed that N215S is a loss-of-function (LOF) variant, while D332G exhibits an hypomorphic behavior. Conversely, H90Y, V219I, A448V, and R902K maintained normal signaling. No skewed X-inactivation was observed in female carriers of N215S or D332G. In addition, the common variants Q11L (rs179008), c.4-151A>G (rs179009) and c.*881C>G (rs3853839) were associated with severe pneumonia, while c.4-151A>G (rs179009) was specifically linked to Intensive Care Unit (ICU) admission. These findings highlight the role of TLR7 in antiviral immune response and its association with severe COVID-19 in men. The luciferase assay proves to be a reliable tool for evaluating TLR7 signaling, effectively distinguishing between neutral, LOF, and gain-of-function (GOF) variants. Further research is needed to better understand TLR7 variants and its implications in immunodeficiency and immune dysregulation.14 p.application/pdfengcc-by (c) Antolí, Arnau et al., 2025http://creativecommons.org/licenses/by/3.0/es/SARS-CoV-2Epidemiologia genèticaSARS-CoV-2Genetic epidemiologyinfo:eu-repo/semantics/article2025-07-10info:eu-repo/semantics/openAccess40423910