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First Author:  Caspar I. van der Made  

Journal/preprint name: JAMA Network 

Paper DOI10.1001/jama.2020.13719 

Tags: TLR7, severe COVID-19, male/female differences   


The authors investigate genomic variations in 2 pairs of young (20-35) brothers suffering from severe COVID-19. They identify a loss of function mutation affecting X-chromosomal TLR7 in one set of brothers that is heterozygous in the carrier mother, and a missense variant in the same gene predicted as deleterious in the second set of brothers. Upon PBMC imiquimod stimulation TLR7 expression is upregulated in healthy controls but not in the patientsTLR7 downstream signalling is impaired, as is IFN-y production in response to imiquimod but not Candida albicans. The authors suggest a vital role for TLR7 in the defence against SARS-CoV-2 and a potential explanation for higher risk of severe disease in males. 

Research Highlights

  1. 4 men from 2 different families with severe COVID-19 show loss of function mutations in TLR7 

  1. both rare TLR7 variants (loss of function and missense mutation) result in defective upregulation of type I IFN–related genes in the TLR7 pathway in response to imiquimod and lack of IFN-y production in response to imiquimod but not Candida albicans 

Impact for COVID-19 research:  

  • TLR7 variability could help in the identification of patients at high risk for severe COVID-19 although loss of function TLR7 varients are rare across the general population 

  • X chromosome linked expression of TLR7 could explain higher levels of basal TLR7 expression in females and higher risk of severe COVID-19 in males 


  • In silico, case seriesin vitro 

  • Key Techniques: Rapid whole exome genome sequencing, peripheral mononuclear blood cell isolation and exposure to imiquimod and heat killed Candida albicans yeast 


  • Very small number of subjects studied, index cases were only compared to parents of family 1 which seemed to have lower TLR7, IRF7, ISG15 and IFNB1 expression than healthy controls. Would have been interesting to also see comparisons to parents from family 2. 

  • In the stimulation of PBMCs with Candida albicans only 1 female and 1 male control were used