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<p><i>TLR7</i>, 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 <i>TLR7</i> variants and susceptibility to severe COVID-19 in a multicentric Spanish cohort. The <i>TLR7</i> gene was sequenced in a cohort of 365 COVID-19 patients, stratified into two groups: one comprising mild and asymptomatic patients, considered as controls (<i>n</i> = 87), and the other consisting of moderate to severely affected patients hospitalized due to COVID-19 pneumonia, considered as cases (<i>n</i> = 278). A total of 152 unique <i>TLR7</i> 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 <i>TLR7</i> 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&gt;G (rs179009) and c.*881C&gt;G (rs3853839) were associated with severe pneumonia, while c.4-151A&gt;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 <i>TLR7</i> variants and its implications in immunodeficiency and immune dysregulation.</p>

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From Rare to Common: Genetic Insights into TLR7 Variants in a Multicentric Spanish Study on COVID-19 Severity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Arnau Antolí,
  • Gardenia Vargas-Parra,
  • Angels Sierra-Fortuny,
  • Jose Luis Gomez-Vazquez,
  • Paula Rofes,
  • Elisabet Munté,
  • Julen Viana-Errasti,
  • Raúl Marín-Montes,
  • Adriana López-Doriga,
  • Lidia Feliubadaló,
  • Jesús del Valle,
  • Alexandre Pérez-González,
  • Eva Poveda,
  • Xavier Solanich,
  • Conxi Lázaro

摘要

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.