TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women

Azar, Pascal; Mejía, José Enrique; Cénac, Claire; Shaiykova, Arnoo; Youness, Ali; Laffont, Sophie; Essat, Asma; Izopet, Jacques; Passaes, Caroline; Müller‐Trutwin, Michaela; Delobel, Pierre; Meyer, Laurence; Guéry, Jean‐Charles

doi:10.1172/jci.insight.136047

Cited by 40 publications

(78 citation statements)

References 65 publications

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“…Female B cells with escape from XCI of TLR7 had higher TLR7 mRNA levels compared to B cells with mono-allelic expression of the gene. Remarkably, TLR7 protein expression was higher in women blood leukocytes compared to men [ 23 ], and this enhanced expression of TLR7 protein in women PBMCs was maintained over ages [ 34 ]. B cell from women stimulated through TLR7 in vitro differentiated more efficiently into CD27 hi plasmablasts than B cells from men, and were enriched in cells with biallelic expression of TLR7 [ 23 ].…”

Section: Candidate X-linked Genes Escaping From XCI With Possible mentioning

confidence: 99%

“…The effect of genotypes may be different between males and females due to certain genetic polymorphisms, or expression quantitative trait loci (eQTL), responsible for sex-specific genetic architecture [ 50 ]. The TLR7 polymorphism rs179008 (NM_016562.3:c.32A>T) has been recently identified as a sex-specific eQTL, causing a difference in functional expression of TLR7 protein and effector function only in females [ 34 ]. The rs179008 is a SNP which introduces a substitution of a leucine for a glutamine (p.Gln11Leu) at the protein level in the leader sequence of TLR7 thereby controlling protein dosage at the translational level through the mRNA sequence itself, rather than through signal peptide function [ 34 ].…”

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

“…The TLR7 polymorphism rs179008 (NM_016562.3:c.32A>T) has been recently identified as a sex-specific eQTL, causing a difference in functional expression of TLR7 protein and effector function only in females [ 34 ]. The rs179008 is a SNP which introduces a substitution of a leucine for a glutamine (p.Gln11Leu) at the protein level in the leader sequence of TLR7 thereby controlling protein dosage at the translational level through the mRNA sequence itself, rather than through signal peptide function [ 34 ]. The minor allele rs179008 T impaired type I interferon production by pDCs in response to TLR7 ligands, but only in women.…”

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

“…Importantly, in a cohort of acute HIV-1 infected women, rs179008 T allele was significantly associated with lower levels of a triad of positively correlated parameters: RNA viral load, the cell-associated HIV-1 DNA reservoir, and plasma IP-10. In addition, the higher frequency of asymptomatic clinical presentations at diagnosis for the T/T homozygous genotype implies a trend for a delayed onset of the symptoms of acute infection, supporting a beneficial effect of toning down TLR7-driven IFN-I production by pDCs during acute HIV-1 infection [ 34 ]. Beside its potential effect in viral infections the rs179008 SNP has been also associated with the susceptibility to SLE [ 52 ].…”

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

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Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Youness

Miquel

Guéry

2021

IJMS

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Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

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Section: Candidate X-linked Genes Escaping From XCI With Possible mentioning

confidence: 99%

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

Section: Interactions Between Sex and Genetic Polymorphism: The Camentioning

confidence: 99%

See 2 more Smart Citations

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Youness

Miquel

Guéry

2021

IJMS

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“…To validate our aproach, we analyzed the ultrasensitive p24 quantification in 92 plasma samples from a subcohort of people with primary HIV-1 infection from the ANRS CO6 PRIMO cohort (27). Samples from 92 individuals were analyzed displaying highly variable plasma RNA viral loads (Figure 3A, 48,263 copies/mL [24 – 211,360,000]).…”

Section: Resultsmentioning

confidence: 99%

Ultrasensitive detection of p24 in plasma samples from people with primary and chronic HIV-1 infection

Passaes

Delagrèverie

Avettand-Fènoël

et al. 2021

Preprint

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HIV-1 Gag p24 has long been identified as an informative biomarker of HIV replication, disease progression and therapeutic efficacy, but the lower sensitivity of immunoassays in comparison to molecular tests and the interference with antibodies in chronic HIV infection limits its application for clinical monitoring. The development of ultrasensitive protein detection technologies may help overcoming these limitations. Here we evaluated whether immune-complex dissociation combined with ultrasensitive digital ELISA Simoa technology could be used to quantify p24 in plasma samples from people with HIV-1 infection. We found that, among different immune-complex dissociation methods, only acid-mediated dissociation was compatible with ultrasensitive p24 quantification by digital ELISA, strongly enhancing p24 detection at different stages of HIV-1 infection. We show that ultrasensitive p24 levels correlated positively with plasma HIV-RNA and HIV-DNA and negatively with CD4+ T cells in the samples from people with primary and chronic HIV-1 infection. In addition, p24 levels also correlated with plasma D-dimers and IFNα levels. P24 levels sharply decreased to undetectable levels after initiation of combined antiretroviral treatment (cART). However, we identified a group of people who, 48 weeks after cART initiation, had detectable p24 levels despite having undetectable viral loads. These people had different virologic and immunologic baseline characteristics when compared with people who had undetectable p24 after cART. These results demonstrate that ultrasensitive p24 analysis provides an efficient and robust mean to monitor p24 antigen in plasma samples from people with HIV-1 infection, including during antiretroviral treatment, and may provide complementary information to other commonly used biomarkers.ImportanceThe introduction of combined antiretroviral treatment has transformed HIV-1 infection in a manageable condition. In this context, there is a need for additional biomarkers to monitor HIV-1 residual disease or the outcome of new interventions, such as in the case of HIV cure strategies. The p24 antigen has a long half-live outside viral particles and it is therefore a very promising marker to monitor episodes of viral replication or transient activation of the viral reservoir. However, the formation of immune-complexes with anti-p24 antibodies difficult its quantification beyond acute HIV-1 infection. We show here that, upon immune-complex dissociation, new technologies allow the ultrasensitive p24 quantification in plasma samples throughout HIV-1 infection, at levels close to that of viral RNA and DNA determinations. Our results further indicate that ultrasensitive p24 quantification may have added value when used in combination with other classic clinical biomarkers.

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Presence of Genetic Variants Among Young Men With Severe COVID-19

Made

Simons

Schuurs-Hoeijmakers

et al. 2020

JAMA

695

623

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IMPORTANCESevere coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).OBJECTIVE To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSCase series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.EXPOSURE Severe COVID-19. MAIN OUTCOME AND MEASURESResults of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. RESULTSThe 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c. 2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. CONCLUSIONS AND RELEVANCEIn this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

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TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women

Cited by 40 publications

References 65 publications

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Ultrasensitive detection of p24 in plasma samples from people with primary and chronic HIV-1 infection

Presence of Genetic Variants Among Young Men With Severe COVID-19

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