tetano
Editor, Senior Moderator
J Clin Immunol
. 2025 May 27;45(1):100.
doi: 10.1007/s10875-025-01892-0. From Rare to Common: Genetic Insights into TLR7 Variants in a Multicentric Spanish Study on COVID-19 Severity
Arnau Antolí[SUP] 1 2 3 4 [/SUP], Gardenia Vargas-Parra[SUP] #[/SUP][SUP] 5 6 7 [/SUP], Angels Sierra-Fortuny[SUP] #[/SUP][SUP] 1 3 [/SUP], Jose Luis Gomez-Vazquez[SUP] 1 3 4 [/SUP], Paula Rofes[SUP] 5 6 7 [/SUP], Elisabet Munté[SUP] 5 6 7 [/SUP], Julen Viana-Errasti[SUP] 6 [/SUP], Raúl Marín-Montes[SUP] 6 8 [/SUP], Adriana López-Doriga[SUP] 8 9 [/SUP], Lidia Feliubadaló[SUP] 5 6 7 [/SUP], Jesús Del Valle[SUP] 5 6 7 [/SUP], Alexandre Pérez-González[SUP] 10 11 [/SUP], Eva Poveda[SUP] 11 [/SUP], Xavier Solanich[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Conxi Lázaro[SUP] #[/SUP][SUP] 12 13 14 15 [/SUP]
Affiliations
TLR7, 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.
Keywords: COVID-19; TLR7; X-linked; immunodeficiency; innate immunity.
. 2025 May 27;45(1):100.
doi: 10.1007/s10875-025-01892-0. From Rare to Common: Genetic Insights into TLR7 Variants in a Multicentric Spanish Study on COVID-19 Severity
Arnau Antolí[SUP] 1 2 3 4 [/SUP], Gardenia Vargas-Parra[SUP] #[/SUP][SUP] 5 6 7 [/SUP], Angels Sierra-Fortuny[SUP] #[/SUP][SUP] 1 3 [/SUP], Jose Luis Gomez-Vazquez[SUP] 1 3 4 [/SUP], Paula Rofes[SUP] 5 6 7 [/SUP], Elisabet Munté[SUP] 5 6 7 [/SUP], Julen Viana-Errasti[SUP] 6 [/SUP], Raúl Marín-Montes[SUP] 6 8 [/SUP], Adriana López-Doriga[SUP] 8 9 [/SUP], Lidia Feliubadaló[SUP] 5 6 7 [/SUP], Jesús Del Valle[SUP] 5 6 7 [/SUP], Alexandre Pérez-González[SUP] 10 11 [/SUP], Eva Poveda[SUP] 11 [/SUP], Xavier Solanich[SUP] #[/SUP][SUP] 1 2 3 4 [/SUP], Conxi Lázaro[SUP] #[/SUP][SUP] 12 13 14 15 [/SUP]
Affiliations
- PMID: 40423910
- PMCID: PMC12116960
- DOI: 10.1007/s10875-025-01892-0
TLR7, 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.
Keywords: COVID-19; TLR7; X-linked; immunodeficiency; innate immunity.