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

Abstract

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

“…Results from the severe COVID-19 outcome analyses of TLR7 with other masks also nearly reach our statistical significance threshold, with larger effects found in the pLoF mask (OR: 13.6, 95% CI: 4.41-44.3, p=1.64×10 -5 ) and smaller effect in the coding1 mask (OR: 3.12, 95% CI: 1.91-5.10, p=5.30×10 -6 ), though the latter was balanced by smaller standard errors due to the larger number of cases (3275 cases in coding1 vs 1577 in pLoF), as expected. These findings further support previous reports of TLR7 errors of immunity underlying severe COVID-19 presentations 17,27–30 .…”

“…Other methods may be needed in future analysis to soften this assumption, though some of these cannot be easily meta-analyzed across multiple cohorts directly from summary statistics (e.g., SKAT-O 41 ). Similarly, methods that combine both rare and common variants might also provide additional insights into disease outcomes 30,42 . Second, our results highlight the importance at looking at different categories of variants through different masks to increase sensitivity and specificity of our burden tests.…”

What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection?

“…The impaired signal pathways of TLR7 were associated with the changes of mRNA CXCL10. It was reported that the CXCL10 mRNA was significantly decreased in two rare variants of TLR7: 920Lys and Asp41Glu in patients with SARS-CoV-2 infection in comparison to healthy donors [ 61 ]. The Described study is in accordance with previous findings focusing on the role of TLR7 and CXCL10, which is directly associated with TLR7 in severe course of COVID-19 [ 59 , 61 ].…”

The human genetic epidemiology of COVID-19

“…This finding has been replicated by Fallerini et al 7 in 561 individuals and Asano et al 5 in a larger sample of 1,533 individuals. Both studies and a further follow-up study by Mantovani et al 43 performed functional investigations highlighting the role of TLR7 loss of function in impaired type I interferon responses.…”