Biology subjects

Venet, F.

Publications and source records attributed to Venet, F..

6 recordsLinked to original sources

bioRxiv2026

Functional alterations of immune gene expression in ICU and non-ICU patients with Legionnaires' disease, a prospective observational study

Legionnaires disease (LD), a pneumonia caused by Legionella pneumophila intracellular bacterium, leads to intensive care unit (ICU) admission in 20-40% of cases. While these ICU-LD patients display severe lung injury or septic shock, their functional immune response remains poorly understood. The present study aimed, through a large immune gene expression assessment, to improve the understanding of immune cell functionality after whole blood LPS ex vivo stimulation in ICU-LD patients compared with non-ICU. Both ICU and non-ICU-LD displayed altered gene expression indicating that both patients immune cells are less able to respond to the LPS ex vivo stimulus than a healthy population. ICU-LD patients had 1.6-fold greater number of less-expressed genes (35/93 vs 22/93, p=0.039), and lower Log2(FC) of these genes (median [IQR]: -1.9 [-2.6;-1.5] vs -1.2 [-1.7;-0.9], p=0.0011) than non-ICU-LD. Seven genes were significantly less expressed by ICU-LD patients (IRF7, MX1, NFKBI2, NFKBIA, RELB, SRC, TIM3; p-value range: 0.029-0.0080). Top five gene ontology biological processes, subcellular localisations, and reactome pathways (STRING database) uniquely enriched in ICU-LD-patients and related less-expressed genes were cellular response to LPS (CCL2, NFKBIA, IRAK2, TIM3, SRC, NFKB1), regulation of IFN-{beta} production (IRF7, RIG1, OAS2, RELB), I-{kappa}B/NF-{kappa}B complex (NFKBIA, NFKB1, NFKB2), IFN regulatory factor complex (RIG1, IRF7), and TRAF6-mediated NF-{kappa}B activation pathway (NFKBIA, NFKB1, NFKB2, RIG1). Immune gene expression alterations in LD after LPS stimulation were found herein, with more pronounced alterations in ICU-LD patients. A reduced expression of key genes and pathways involved in controlling Legionella proliferation in ICU-LD patients may contribute to increased disease severity.

immunology↗

bioRxiv2023

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease (NLRP3-AID or CAPS) is an heterogenous group of monogenic autoinflammations associated with NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants is a barrier to diagnosis although patients can be efficiently treated with anti-IL-1 approaches. In addition, while NLRP3 inflammasome is controlled by coordinated priming and activation signals, gain-of-functions of NLRP3 variants have been only investigated in response to priming. Here, we functionally characterize 34 NLRP3 variants in vitro by determining their activity in response to induction, priming and/or activation signals, and their sensitivity to inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on their profile of signals required for their activation, that correlate partly with the symptoms severities. We identify a new group of NLRP3 mutants responding to the activation signal without priming, with patients often misdiagnosed. Our results identify key NLRP3 residues controlling the inflammasome activity and sensitivity to inhibitors. The comparison of four inhibitors on the 34 variants identifies inhibitory mechanisms with broader efficiency for future drug design. Altogether, our results provide new insights on NLRP3 activation and an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and anti-inflammatory disease drug development. eTOC SummaryFunctional characterization of 34 CAPS-associated NLRP3 variants identifies polymorphisms versus gain-of-function pathogenic mutants, and highlights diversities in the signals controlling their activation and in their sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.

immunology↗

bioRxiv2023

A dynamic inflammation model for neutrophil and monocyte responses in sepsis, trauma and surgery patient clusters.

Time series clustering is applied to inflammation and neutrophil cell development markers, CD16 and CD10, in sepsis, trauma and surgery patients and a dynamical model with an inflammation function, F, is used to represent their evolution over a two month period. Five patient clusters are identified, characterised and evaluated against medical assessment scores and the literature. A dynamical model for neutrophil and monocyte cell counts and maturity has been constructed based on mass balances and cell kinetics in both blood and bone marrow. Cell proliferation and flow rates, as well as expression of monocyte HLA-DR, depend on concentrations of pro- and anti- inflammatory cytokines, IL6 and IL10, via F. A good fit with the data is obtained for each cluster and the estimated parameters correlate to illness severity. The model is a potential tool for simulation of immunomodulatory therapies.

bioengineering↗

bioRxiv2019

Immune Profiling Panel: a proof of concept study of a new multiplex molecular tool to assess the immune status of critically-ill patients

BackgroundCritical illness such as sepsis is a life-threatening syndrome defined as a dysregulated host response to infection and is characterized by patients exhibiting various impaired immune profiles. In the field of diagnosis, a gap still remains in identifying the immune profile of critically-ill patients in the ICU. The availability of an immune profiling tool holds a great potential in providing patients at high risk with more accurate and precise management. In this study, a multiplex immune profiling panel prototype was assessed for its ability to semi-quantify immune markers directly from blood, using the FilmArray(R) System.\n\nResultsThe Immune Profiling Panel (IPP) prototype consists of 16 biomarkers that target both the innate and adaptive immune responses, pro- and anti-inflammatory mediators as well as genes involved in diverse regulatory pathways. The analytical studies carried out on healthy volunteers showed minimal inter- and intra-variability in testing the samples across the tested lots. The majority of the assays were linear with an R2 higher than 0.8. Results from the IPP pouch were comparable to qPCR and were within the limits of agreement. Finally, quantification cycle values of the target genes were normalized against reference genes to account for the different composition of cells among specimens. The use of the selected panel of markers in IPP demonstrated various gene modulations that could distinctly differentiate three profiles: healthy, borderline mHLA-DR septic shock patients and low mHLA-DR septic shock patients.\n\nConclusionThe Immune Profiling Panel allowed host transcriptomic analysis of immune response biomarkers directly from whole blood in less than an hour. The use of IPP showed great potential for the development of a fully automated, rapid and easy-to-use immune profiling tool, enabling the stratification of critically-ill patients at high risk in the ICU.

immunology↗

bioRxiv2018

Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn.

Although human endogenous retroviruses (HERVs) expression is a growing subject of interest, no study focused before on specific endogenous retroviruses loci activation in severely injured patients. Yet, HERV reactivation is observed in immunity compromised settings like some cancers and auto-immune diseases. Our objective was to assess the transcriptional modulation of HERVs in burn, trauma and septic shock patients. We analyzed HERV transcriptome with microarray data from whole blood samples of a burn cohort (n=30), a trauma cohort (n=105) and 2 septic shock cohorts (n=28, n=51), and healthy volunteers (HV, n=60). We described expression of the 337 probesets targeting HERV from U133 plus 2.0 microarray in each dataset and then we compared HERVs transcriptional modulation of patients compared to healthy volunteers. Although all 4 cohorts contained very severe patients, the majority of the 337 HERVs was not expressed (around 74% in mean). Each cohort had differentially expressed probesets in patients compared to HV (from 19 to 46). Strikingly, 5 HERVs were in common in all types of severely injured patients, with 4 being up-modulated in patients. We highlighted co-expressed profiles between HERV and nearby gene as well as autonomous HERV expression. We suggest an inflammatory-specific HERV transcriptional response, and importantly, we introduce that the HERVs close to immunity-related genes might have a role on its expression.

immunology↗

bioRxiv2017

Decreased intra-lymphocyte cytokines measurement in septic shock patients: a proof of concept study in whole blood

Functional testing protocols are thought to be the gold standard for the exploration of the immune system. However, in terms of routine analysis, they present numerous drawbacks and consequently their use is mainly limited to research applications. In the clinical context of septic shock, characterized by marked lymphocyte alterations, a new approach for lymphocyte intracellular cytokine measurement in whole blood upon was evaluated in a proof-of-concept study. Following lymphocyte activation, simultaneous intracellular labeling of Interferon-{gamma} (IFN-{gamma}), Tumor Necrosis Factor- (TNF-), and Interleukin-2 (IL-2) was performed in CD4+ and CD8+ T cells (identified by surface marking). The analysis was carried out by flow cytometry (6 colors). Results obtained in septic patients (n = 22) were compared to those of healthy volunteers (n = 8). Independently of lymphopenia, there were significant differences between groups. In particular there was significant decrease in the production of IL-2 and TNF- in septic patients, while the production of IFN-{gamma} was not significantly altered. Polyfunctional results showed that patients presented with increased percentages of triple negative lymphocytes. In contrast, volunteers had higher proportions of triple positive cells. The approach could be performed in a robust and consistent way, taking 4.5 hours to complete. Moreover, clear differences could be observed between clinical groups with this modified method. These characteristics illustrate the potential of this novel whole blood protocol for clinical applications. However, further research is required to determine the applicability compared to alternative test and to evaluate clinical performances in larger cohorts of patients.

immunology↗