Biology subjects

Bigot, J.

Publications and source records attributed to Bigot, J..

7 recordsLinked to original sources

bioRxiv2026

Integrin beta 1 and mannose receptor 2 are involved in the antifungal activity of bronchial epithelial cells through Aspergillus fumigatus lectin FleA interactions

Aspergillus fumigatus is a world-wide saprophyte filamentous fungus which released conidia, its infectious morphotype, in the atmosphere. These conidia are inhaled daily by humans and can colonize the respiratory tract, where they may develop into hyphae, the invasive morphotype. We previously showed that bronchial epithelial cells (BECs) restrict A. fumigatus virulence by inhibiting conidial germination and filament formation through a process requiring PI3K signaling and the conidial fucose-specific lectin FleA. In the present study, we are looking to identify host factors and cellular partners involved in the BEC antifungal response and to define the molecular interactions underpinning FleA recognition. For this, we analyzed transcriptome of BECs infected with A. fumigatus in the presence or absence of the PI3K inhibitor LY294002. Functional involvement of candidate genes was assessed by siRNA knockdown and readouts of fungal filamentation (microscopic scoring and galactomannan release). FleA-interacting host proteins were identified by biotin-FleA affinity co-precipitation coupled to Tandem mass spectrometry, and validated by surface plasmon resonance and biolayer interferometry. The spatiotemporal dynamics of FleA and candidate partners were analyzed by confocal microscopy and proximity ligation assay We demonstrated that BEC antifungal activity involves at least two complementary pathways: a PI3K/laminin-332 axis promoting conidial adhesion, and a FleA-dependent pathway engaging ITGB1 and MRC2 consistent with lectin uptake and trafficking toward LAMP1-positive compartments. These findings nominate FleA-host receptor interactions as attractive targets for anti-adhesive strategies against A. fumigatus. Author summaryFungal pathogens are an increasing threat to public health, as they are becoming more common and harder to treat due to rising drug resistance. Among them, Aspergillus fumigatus has been classified as a critical pathogen by the World Health Organization (WHO). This filamentous fungus delivers spores in the air daily, which are constantly inhaled by humans. In people with weakened immunity, these spores can cause a range of lung diseases known as aspergillosis, with severity ranging from mild to life-threatening. Lung epithelial cells are the first cells of the respiratory tract to encounter inhaled spores. In a previous study, we showed that bronchial cells can prevent spore from developing into filaments, the invasive form of A. fumigatus that is responsible for tissue damage. This protective effect depends of on the recognition of a fungal protein called FleA. In the present study, we identified host cell proteins that bind to FleA and transport it into intracellular compartments. Our findings suggest that these proteins help bronchial epithelial cells to internalize fungal spores, thereby blocking their transformation into the invasive filamentous form.

cell biology↗

bioRxiv2026

Hijacking of inflammasome responses by the complement system during Pseudomonas aeruginosa-Aspergillus fumigatus sur-infection

Patients with cystic fibrosis (pwCF) are highly susceptible to chronic pulmonary infections due to mutations in the CFTR gene. From early childhood, pwCF experience repeated lung infections and often develop chronic bacterial and/or fungal colonization. Among the most clinically relevant pathogens, Pseudomonas aeruginosa and Aspergillus fumigatus frequently co-infect and are associated with worse outcomes, including excessive IL-1{beta}-driven inflammation and accelerated lung function decline. Here we investigated the mechanisms underlying inflammasome overactivation during super-infection. We found that inflammasome hyperactivation occurred across macrophage populations, was independent of exogenous priming, and required live co-infection with both pathogens. P. aeruginosa and A. fumigatus cooperatively activated the NLRP3 inflammasome, and this response required both caspase-1 and caspase-8. Unexpectedly, gasdermin D was dispensable for IL-1{beta} release. Bacterial flagellin, type IV pili and the type III secretion system, as well as the fungal polysaccharide galactosaminogalactan (GAG), were each required for overactivation. Mechanistically, P. aeruginosa activated the MyD88-TLR pathway, enhancing macrophage responses and promoting ITGAM (CD11b) expression. Under fungal super-infection, macrophages secreted complement component C3, which may bound fungal surface and engaged the complement receptor C3R (CD11b/CD18). Downstream SYK and ERK signaling amplified inflammasome activation and IL-1{beta} release. Single-cell transcriptomic analysis of pwCF broncho-alveolar lavage and lung samples supported coordinated upregulation of complement and inflammasome pathways during bacterial-fungal infection. Together, these findings identify a complement-inflammasome signaling axis that drives pathological inflammation during bacterial-fungal co-infection in airways of pwCF and may represent a therapeutic target.

immunology↗

bioRxiv2025

Targeting glucocorticoid-induced CD20 activation in preclinical models of B-ALL

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is effectively controlled with contemporary multi-agent chemotherapy, resulting to 5-year survival rates above 90%. However, relapse occurs in 15-20% of patients due to minimal residual disease (MRD), characterized by the presence of persisting and resistant leukemic cells, and associated with a poor clinical outcome. Despite its prognostic relevance, the molecular features driving MRD are poorly characterized. In this study, we developed patient-derived xenograft (PDX) models from matched diagnosis and relapse B-ALL samples combined to chemotherapy to mimic MRD in vivo. Drug-tolerant leukemic cells were profiled using single-cell RNA sequencing and we identified a transcriptionally distinct MRD-like population enriched for cell-quiescence, inflammatory stress, and B-cell receptor pathway signatures. Strikingly, the B-lymphocyte surface antigen CD20, encoding by MS4A1 gene, emerged as a consistent upregulated marker in MRD cells from PDXs and patients with diverse oncogenic subtypes. We further demonstrated that CD20 expression is induced by glucocorticoid exposure, creating a therapeutic opportunity where anti-CD20 monoclonal antibodies selectively eradicated MRD cells in vivo. Our data highlight CD20 not only as a biomarker but as an actionable vulnerability in B-ALL MRD, supporting clinical evaluation of anti-CD20 immunotherapy during induction treatment to kill drug-resistant cells and reduce relapse risk.

cancer biology↗

bioRxiv2025

The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity

BackgroundInnate immune memory, also called trained immunity, refers to the ability of innate immune cells to gain memory characteristics after transient stimulation, resulting in a nonspecific modified inflammatory response upon secondary remote challenge. Bronchial epithelial cells (BECs) participate in innate immune defence and are the first cells of the lower respiratory tract to encounter inhaled pathogens. We recently showed that BECs are capable of innate immune memory after preexposure to Pseudomonas aeruginosa flagellin through epigenetic mechanisms. In the present study, we investigated such mechanisms through the modification of chromatin architecture induced by flagellin preexposure that results in subsequent changes of gene expression. ResultsBy conducting an unsupervised approach to jointly analyse chromatin accessibility and gene expression, we mapped the remodelling of the epigenomic and transcriptomic profiles during the establishment of BECs memory. We identified a Memory regulatory profile induced by flagellin exposure. It includes clusters of upregulated genes related to inflammation that are linked to a sustainable gain in chromatin accessibility and with an increased activity of specific factors (TFs) whose binding may drive this process. ConclusionsIn summary, we demonstrated that flagellin exposure induced changes in chromatin condensation in BECs, which sustains the reprogramming of transcriptional patterns

genetics↗

bioRxiv2024

New insights into the echinocandin resistance in Candida spp. in the clinical setting

Despite a huge consumption of echinocandins, the emergence of resistance in Candida spp has remained overall limited. Here, we depicted the epidemiology of Candida spp in our center face to the echinocandins consumption. We postulate new hypotheses that may explain the shaping of candines resistance in the clinical setting. Epidemiology of Candida infections and echinocandin consumption were evaluated in our center over 12 years (2006-2018). Glucan synthase genes (fks1, fks2) were sequenced. The in vitro fitness was assessed for couple of isogenic strains, of which one was resistant. Finally, the modelling of Candida FKS proteins was realized. Despite a three-fold increase in echinocandin consumption, no significant emergence of resistance was observed. In Candida albicans, fks1 mutations affect the three-dimensional conformation of the glucan synthase, which may result in altered export of the glucan chain, which could explain the observed reduced fitness. In contrast, cross-complementation between FKS1 and FKS2 in Nakaseomyces glabratus might circumvent the negative impact on fitness. ConclusionsOur results support the fact that N. glabratus is more prone to the spread of echinocandin-resistant strains. The link between mutations in the glucan synthase and fitness of Candida strains might explain the difference in the species-specific emergence of echinocandins-resistant strains.

microbiology↗

bioRxiv2023

Molecular epidemiology of Candida africana isolates collected from vagina swabs in French Guiana.

Candida africana corresponds to the clade 13 of Candia albicans. It has been mostly involved in vulvovaginal candidiasis worldwide but few data exist in South America. The aim of our study was to investigate the prevalence of C. africana in women living in French Guiana. For this, we first set up a fluorescent-intercalating-dye-real time PCR targeting the hyphal wall protein 1 gene. The test was applied to 212 C. albicans isolates collected from May to August 2019 from vaginal swabs, allowing the identification of 6 women harboring C. africana (8 isolates). No demographics or clinical-specific features could be demonstrated. Genetic diversity of those isolates was analyzed through multilocus sequence typing and showed that diploid sequence type 182 was predominant (n=6) and allowed the report of a new diploid sequence type.

microbiology↗

bioRxiv2020

Flagellin from Pseudomonas aeruginosa increases the expression of the SARS-CoV2 entry protease TMPRSS2 in airway epithelial cells

The major challenge of the COVID-19 health crisis is to identify the factors of susceptibility to SARS-Cov2 in order to adapt the recommendations to the populations and to reduce the risk of getting COVID-19 to the most vulnerable people especially those having chronic respiratory diseases including cystic fibrosis (CF). Airway epithelial cells (AEC) are playing a critical role in the immune response and in COVID-19 severity. SARS-CoV-2 infects the airways through ACE2 receptor and the host protease TMPRSS2 was shown to play a major role in SARS-CoV-2 infectivity. Here, we show that the main component of P. aeruginosa flagella, ie. flagellin is able to increase TMPRSS2 expression in AEC, and even more in those deficient for CFTR. Importantly, this increased TMPRSS2 expression is associated with an increase in the level of SARS-CoV-2 infection. Considering the urgency of the health situation, this result is of major significance for patients with CF which are frequently infected and colonized by P. aeruginosa during the course of the disease.

pathology↗