Biology subjects

Guillemot, V.

Publications and source records attributed to Guillemot, V..

7 recordsLinked to original sources

bioRxiv2024

IL-23 tunes inflammatory functions of human mucosal-associated invariant T (MAIT) cells

IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human MAIT, but not of conventional T cells. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomic and chromatin accessibility, supported by CRISPR/Cas9 mediated deletion, shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells. In conclusion, our findings indicate that MAIT cells are key mediators of IL-23 functions in immunity to infections and chronic inflammatory diseases.

immunology↗

bioRxiv2022

Alterations of the axon initial segment in multiple sclerosis

Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analyzed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e., axon initial segment length and position. We found that the axon initial segment length was unchanged among the different multiple sclerosis samples, and not different from controls. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show for the first time changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.

neuroscience↗

bioRxiv2021

The genetic architecture of language functional connectivity

Language is a unique trait of the human species, of which the genetic architecture remains largely unknown. Through language disorders studies, many candidate genes were identified. However, such complex and multifactorial trait is unlikely to be driven by only few genes and case-control studies, suffering from a lack of power, struggle to uncover significant variants. In parallel, neuroimaging has significantly contributed to the understanding of structural and functional aspects of language in the human brain and the recent availability of large scale cohorts like UK Biobank have made possible to study language via image-derived endophenotypes in the general population. Because of its strong relationship with task-based fMRI activations and its easiness of acquisition, resting-state functional MRI have been more popularised, making it a good surrogate of functional neuronal processes. Taking advantage of such a synergistic system by aggregating effects across spatially distributed traits, we performed a multivariate genome-wide association study (mvGWAS) between genetic variations and resting-state functional connectivity (FC) of classical brain language areas in the inferior frontal (pars opercularis, triangularis and orbitalis), temporal and inferior parietal lobes (angular and supramarginal gyri), in 32,186 participants from UK Biobank. Twenty genomic loci were found associated with language FCs, out of which three were replicated in an independent replication sample. A locus in 3p11.1, regulating EPHA3 gene expression, is found associated with FCs of the semantic component of the language network, while a locus in 15q14, regulating THBS1 gene expression is found associated with FCs of the perceptualmotor language processing, bringing novel insights into the neurobiology of language.

genetics↗

bioRxiv2021

Cell-type specific innate immune responses shape rabies virus tropism

Viral tropism, or the specificity of a particular virus to infect a certain cell type, is crucial in determining virus replication, viral spread, and ultimately host survival. Rabies, one of the deadliest known zoonotic diseases, is still causing 60.000 human deaths annually. Upon central nervous system (CNS) entry, neurotropic rabies virus (RABV) preserves the neural network by limiting apoptosis and inflammation. To date, we do not fully understand the factors determining RABV tropism and why glial cells are unable to clear RABV from the infected brain. Here, we compare susceptibilities and innate immune responses of CNS cell types towards infection with virulent dog RABV Tha and less virulent Th2P-4M in vitro, highlighting differences in cellular susceptibility and antiviral responses. Less virulent Th2P-4M bears mutations introduced in viral phosphoprotein (P-protein) and matrix protein (M-protein) thereby hindering viral immune evasion of the host nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and Janus kinase (JAK) - signal transducer and activator of transcription protein (STAT) pathways. Our results reveal that human neural stem cell (hNSC)-derived neurons and astrocytes, in contrast to human iPSC-derived microglia, are highly susceptible to Tha and Th2P-4M infection in vitro. Surprisingly, Th2P-4M presents a stronger neurotropism in hNSC-derived CNS cultures compared to Tha suggesting that NF-{kappa}B- and JAK-STAT-mediated antiviral host responses are defining RABV replication and thereby its tropism. Further, we show that astrocyte-like (SVGp12) and microglia-like (HMC3) cells protect neuroblastoma cells (SK-N-SH) from Tha infection in vitro. Transcription profiles and quantification of intracellular protein levels revealed major differences in antiviral immune responses mediated by neurons, astrocytes (IFNB1, CCL5, CXCL10, IL1B, IL6, LIF), and microglia (CCL5, CXCL10, ISG15, MX1, IL6) upon virulent Tha infection. Overall, we provide evidence that RABV tropism depends on its capability to evade cell-type specific immune responses via P- and M-proteins. Author summaryRabies virus (RABV) neurotropism is widely reported as a unique feature of rabies, and still the exact mechanism underlying RABV susceptibility remains to be elucidated. Several receptors are known to accelerate RABV entry to the cell (1-4) and yet, none of them seems to be essential for successful infection (5,6) questioning a marked cellular tropism. Although RABV is classically reported as strictly neurotropic (7), recent studies report profound infection of glial cells in vivo depending on the viral strain and the infection route used (8,9). Here, we provide evidence that human neural stem cell (hNSC)-derived neurons (hiNeurons) and astrocytes (hiAstrocytes) are highly susceptible towards infection with the virulent field RABV strain Tha and less virulent Th2P-4M. In contrast, human iPSC-derived microglia-like cells (hiMicros) are resistant to viral replication in vitro. Whereas hiNeurons are immunologically quiescent upon Tha infection, fetal astrocytes and hiMicros establish strong antiviral responses. In contrast to Tha, Th2P-4M, which is unable to evade NF-{kappa}B and JAK-STAT pathways (10), shows a more profound neurotropism suggesting that cell-type specific responses shape RABV tropism. Hence, we conclude that viral evasion mechanisms mediated by P- and M-proteins partly determine Tha tropism of human CNS cell types in vitro.

microbiology↗

bioRxiv2020

Multitrait genetic-phenotype associations to connect disease variants and biological mechanisms

BackgroundGenome-wide association studies (GWAS) uncovered a wealth of associations between common variants and human phenotypes. These results, widely shared across the scientific community as summary statistics, fostered a flurry of secondary analysis: heritability and genetic correlation assessment, pleiotropy characterization and multitrait association test. Amongst these secondary analyses, a rising new field is the decomposition of multitrait genetic effects into distinct profiles of pleiotropy. ResultsWe conducted an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link to biological mechanisms. We started by benchmarking multitrait association tests on a large panel of phenotype sets and established the Omnibus test as the most powerful in practice. We detected 322 new associations that were not previously reported by univariate screening. Using independent significant associations, we investigated the breakdown of genetic association into clusters of variants harboring similar multitrait association profile. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how SNPs within clusters can be mapped to biological pathways and disease mechanisms, providing a putative insight for numerous SNPs with unknown biological function. Finally, for the metabolism set, we investigate the link between gene cluster assignment and success of drug targets in random control trials. We report additional uninvestigated drug targets classified by clusters. ConclusionsMultitrait genetic signals can be decomposed into distinct pleiotropy profiles that reveal consistent with pathways databases and random control trials. We propose this method for the mapping of unannotated SNPs to putative pathways.

genetics↗

bioRxiv2019

JASS: Command Line and Web interface for the joint analysis of GWAS results

Genome Wide Association Study (GWAS) has been the driving force for identifying association between genetic variants and human phenotypes. Thousands of GWAS summary statistics covering a broad range of human traits and diseases are now publicly available, and studies have demonstrated their utility for a range of secondary analyses. This includes in particular the joint analysis of multiple GWAS to identify new genetic variants missed by univariate screenings. However, although several methods have been proposed, there are very few large scale applications published so far because of challenges in implementing these methods on real data. Here, we present JASS (Joint Analysis of Summary Statistics), a polyvalent Python package that addresses this need. Our package solves all practical and computational barriers for large-scale multivariate analysis of GWAS summary statistics. This includes data cleaning and harmonization tools, an efficient algorithm for fast derivation of various joint statistics, an optimized data management process, and a web interface for exploration purposes. Benchmark analyses confirmed the strong performances of JASS. We also performed multiple real data analyses demonstrating the strong potential of JASS for the detection of new associated genetic variants across various scenarios. Our package is freely available at https://gitlab.pasteur.fr/statistical-genetics/jass.

bioinformatics↗

bioRxiv2017

Adjusting For Principal Components Of Molecular Phenotypes Induces Replicating False Positives

High-throughput measurements of molecular phenotypes provide an unprecedented opportunity to model cellular processes and their impact on disease. Such highly-structured data is strongly confounded, and principal components and their variants reliably estimate latent confounders. Conditioning on PCs in downstream analyses is known to improve power and reduce multiple-testing miscalibration and is an indispensable element of thousands of published functional genomic analyses. Further clarifying this approach is of fundamental interest to the genomics and statistics communities. We uncover a novel bias induced by PC conditioning and provide an analytic, deterministic and intuitive approximation. The bias exists because PCs are, roughly, unshielded colliders on a causal path: because PCs partially incorporate a causal genotype effect on one phenotype, the genotype becomes correlated with every phenotype conditional on PCs. We empirically quantify this bias in realistic simulations. For small genetic effects, a nearly negligible bias is observed for all tested PC variants. For large genetic effects, or other differential covariates, dramatic false positives can arise. Though one PC variant (supervised SVA) largely avoids this bias, it is computationally prohibitive genome-wide; further, its immunity to this bias is novel. Our analysis informs best practices for confounder correction in genomic studies.

genetics↗