Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
- University of Siena, Italy
- Fondazione IRCCS Policlinico San Matteo, Italy
- University of Pavia, Pavia, Italy
- Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Italy
- University of Brescia and ASST Spedali Civili Hospital, Italy
- Ospedale Maggiore di Crema, Italy
- ASST-FBF-Sacco, Italy
- University of Milan, Italy
- Azienda USL Toscana Sud Est, Italy
Abstract
Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.
Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.
Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.
Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.
Data availability
Sequencing data have been deposited in CINECA through http://www.nig.cineca.it/, specifically, http://nigdb.cineca.it., in the COVID-19 section through http://nigdb.cineca.it./registration/login.php. There are no restrictions on data access. Only registration is needed.
Article and author information
Author details
Alessandra Renieri
Funding
Private Donors for Host Genetics Research Project (D.L. n 18 of March 17)
- Alessandra Renieri
Intesa San Paolo for 2020 charity fund (N.B.2020/0119)
- Alessandra Renieri
Host Genetics Initiative (Dipartimenti di Eccellenza 2018-2020)
- Alessandra Renieri
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The GEN-COVID study was consistent with Institutional guidelines and approved by the University Hospital (Azienda Ospedaliero-Universitaria Senese) Ethical Review Board, Siena, Italy (Prot n. 16929, dated March 16, 2020).
Copyright
© 2021, Fallerini et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,801
- views
-
- 751
- downloads
-
- 159
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
eLife 10:e67569.
https://doi.org/10.7554/eLife.67569
Further reading
-
- Epidemiology and Global Health
- Medicine
- Microbiology and Infectious Disease
eLife has published the following articles on SARS-CoV-2 and COVID-19.
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Polyamines are biologically ubiquitous cations that bind to nucleic acids, ribosomes, and phospholipids and, thereby, modulate numerous processes, including surface motility in Escherichia coli. We characterized the metabolic pathways that contribute to polyamine-dependent control of surface motility in the commonly used strain W3110 and the transcriptome of a mutant lacking a putrescine synthetic pathway that was required for surface motility. Genetic analysis showed that surface motility required type 1 pili, the simultaneous presence of two independent putrescine anabolic pathways, and modulation by putrescine transport and catabolism. An immunological assay for FimA—the major pili subunit, reverse transcription quantitative PCR of fimA, and transmission electron microscopy confirmed that pili synthesis required putrescine. Comparative RNAseq analysis of a wild type and ΔspeB mutant which exhibits impaired pili synthesis showed that the latter had fewer transcripts for pili structural genes and for fimB which codes for the phase variation recombinase that orients the fim operon promoter in the ON phase, although loss of speB did not affect the promoter orientation. Results from the RNAseq analysis also suggested (a) changes in transcripts for several transcription factor genes that affect fim operon expression, (b) compensatory mechanisms for low putrescine which implies a putrescine homeostatic network, and (c) decreased transcripts of genes for oxidative energy metabolism and iron transport which a previous genetic analysis suggests may be sufficient to account for the pili defect in putrescine synthesis mutants. We conclude that pili synthesis requires putrescine and putrescine concentration is controlled by a complex homeostatic network that includes the genes of oxidative energy metabolism.
