Biology subjects

Pardieu, C.

Publications and source records attributed to Pardieu, C..

3 recordsLinked to original sources

bioRxiv2025

Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells

Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of V{gamma}9V{delta}2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated V{delta}2+T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In contrast, Crohns disease (CD) patients with reduced V{delta}2+T-cell numbers displayed outgrowth of C. albicans strains that readily formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1{beta} release ex vivo. Genomic and proteomic analysis of the Candida isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an intestine-on-a-chip model. These data reveal that bacterial activation of V{delta}2+T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.

immunology↗

bioRxiv2025

Microbially-competent skin organotypics reveal dysregulated AhR signalling in microbial dysbiosis

Microbial dysbiosis is increasingly linked to skin disorders, yet the mechanisms driving these pathological processes remain poorly understood. This study developed microbially competent 3D skin organotypics (OTs) representing healthy (5M) and dandruff (5MP) microbiomes, to investigate host-microbial interactions. OTs colonised with 5M microbiota exhibited healthy skin morphology, while 5MP colonised OTs displayed dandruff-like phenotypes, including altered epidermal morphology, reduced barrier protein expression, and dysregulated corneodesmosome hydrolysis. Transcriptomic and protein analysis revealed attenuation of the aryl hydrocarbon receptor (AhR) signalling pathway in 5MP colonised OTs, a finding subsequently validated at the protein level in participants with dandruff. These results strongly suggest that microbial dysbiosis contributes to dandruff pathogenesis through disruption of AhR signalling, a pathway crucial for maintaining epidermal barrier function and immune homeostasis. This in vitro model provides new insights into the role of microbial dysbiosis in skin disorders and could open new avenues for host-microbiome therapeutic interventions.

microbiology↗

bioRxiv2018

HIV-1 Vpr accessory protein interacts with REAF and mitigates its associated anti-viral activity.

The Human Immunodeficiency Virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and in cycling T cells to a lesser extent. Virion packaged Vpr is released in target cells shortly after entry, suggesting its requirement in the early phase of infection. Previously, we described REAF (RNA-associated Early-stage Antiviral Factor, RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without intact vpr is more highly restricted by REAF and, using delivery by VLPs, that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells and we detect, by co-immunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts very quickly during the early phase of replication and induces the degradation of REAF within 30 minutes of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localisation and interaction with cullin4A-DBB1 (DCAF1) E3 ubiquitin ligase is required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, which impedes HIV infection in macrophages.\n\nImportanceFor at least 30 years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1 in vivo. A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages, or to explain why Vpr is carried in the virus particle. Here we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one which inhibits virus replication early during reverse transcription. REAF is degraded by Vpr within 30 minutes of virus entry, in a manner dependent on the nuclear localization of Vpr and its interaction with the cells protein degradation machinery.

microbiology↗