Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients

Toll-like receptors (TLR) are crucial components in the initiation of\r\ninnate immune responses to a variety of pathogens, triggering the\r\nproduction of pro-inflammatory cytokines and type I and II interferons,\r\nwhich are responsible for innate antiviral responses. Among the\r\ndifferent TLRs, TLR7 recognizes several single-stranded RNA viruses\r\nincluding SARS-CoV-2. We and others identified rare loss-of-function\r\nvariants in X-chromosomal TLR7 in young men with severe COVID-19 and\r\nwith no prior history of major chronic diseases, that were associated\r\nwith impaired TLR7 signaling as well as type I and II IFN responses.\r\nHere, we performed RNA sequencing to investigate transcriptome\r\nvariations following imiquimod stimulation of peripheral blood\r\nmononuclear cells isolated from patients carrying previously identified\r\nhypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our\r\ninvestigation revealed a profound impairment of the TLR7 pathway in\r\npatients carrying loss-of-function variants. Of note, a failure in IFN\r\ngamma upregulation following stimulation was also observed in cells\r\nharboring the hypofunctional and hypomorphic variants. We also\r\nidentified new TLR7 variants in severely affected male patients for\r\nwhich a functional characterization of the TLR7 pathway was performed\r\ndemonstrating a decrease in mRNA levels in the IFN alpha, IFN gamma,\r\nRSAD2, ACOD1, IFIT2, and CXCL10 genes.