Biology subjects

Parent, C.

Publications and source records attributed to Parent, C..

24 records · Page 2Linked to original sources

bioRxiv2022

Mucosal administration of anti-bacterial antibody provides long-term cross-protection against Pseudomonas aeruginosa respiratory infection

Bacterial respiratory infections, associated with acute, sometimes recurrent infections and with chronic respiratory diseases, are a major threat for human health. Mucosal administration of therapeutic antibodies (Ab), using the airways as a delivery route, has a tremendous opportunity to benefit to patients with respiratory infections, with remarkable preclinical achievements in both viral and bacterial respiratory infection models and ongoing clinical developments. The primary mode of action of anti-infective Ab delivered through the airways is pathogen neutralization and to a lesser extent, Fc-mediated direct recruitment of immune effectors to facilitate their elimination. Using a mouse model of acute pneumonia induced by P. aeruginosa, a bacterium frequently associated with multidrug resistance and a high rate of recurrence, we characterized an immunomodulatory mode of action of anti-bacterial Ab. Beyond the rapid and efficient containment of the primary infection, the anti-infective Ab delivered through the airways harnessed adaptive immunity to provide a long-term response, preventing from a secondary pathogen infection. This effect is specific and dependent on the Ab dose, intensity of infection and antigen expression by the pathogen upon primary infection. As shown by adoptive transfer experiments, it is mediated by a sustained and protective humoral immune response. Interestingly, the long-lasting response protected partially against secondary infections due to heterologous P. aeruginosa strains. Overall, our findings suggest that mucosal delivery of Ab through the airways offers a dual advantage: a rapid onset of action to neutralize respiratory bacteria and a long-term protection against secondary infections, thereby opening novel perspectives for the development of anti-infective antibody delivered to the lung mucosa, to treat respiratory infections.

immunology↗

bioRxiv2022

Ceramide-Rich Microdomains Facilitate Nuclear Envelope Budding during the Biogenesis of LTB4-containing Exosomes

Neutrophils migrating towards chemoattractant gradients amplify their recruitment range by releasing the secondary chemoattractant leukotriene B4 (LTB4)1,2. We previously demonstrated that LTB4 and its synthesizing enzymes, the 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP), and leukotriene A4 hydrolase (LTA4H), are packaged and released in exosomes3. We now report that the biogenesis of the LTB4-containing exosomes is initiated at the nuclear envelope (NE) of activated neutrophils. We show that the neutral sphingomyelinase 1 (nSMase1)-mediated generation of ceramide enriched lipid-ordered microdomains initiates the clustering of the LTB4-synthesizing enzymes on the NE. We isolated and analyzed exosomes from activated neutrophils and established that the FLAP/5-LO-positive exosome population is distinct from that of the CD63-positive exosome population. Furthermore, we observed a strong co-localization between ALIX and FLAP at the periphery of nuclei and within cytosolic vesicles. We propose that the initiation of NE curvature and bud formation is mediated by nSMase1-dependent ceramide generation, which leads to FLAP and ALIX recruitment. Together, these observations elucidate the mechanism for LTB4 secretion and identify a novel pathway for exosome generation.

cell biology↗

bioRxiv2021

Genomic Modules and Intramodular Network Convergency of Susceptibility and Resilience in Multimodeled Stress in Male Mice

The multifactorial etiology of stress-related disorders is a challenge in developing synchronized medical standards for treatment and diagnosis. It is largely unknown whether there exists molecular convergence in preclinical models of stress generated using disparate construct validity. Using RNA-sequencing (RNA-seq), we investigated the genomic signatures in the ventral hippocampus, which mostly regulates affective behavior, in mouse models that recapitulate the hallmarks of anxiety and depression. Chronic oral corticosterone (CORT), a model that causes a blunted endocrine response to stress, induced anxiety- and depression-like behavior in wildtype mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor (BDNF) Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of mice, chronic social defeat stress led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, standard housing or enriched environment. A rank-rank-hypergeometric (RRHO) analysis of the RNA-seq data set across models demonstrated that in mice treated with CORT and susceptible mice raised in standard housing differentially expressed genes (DEGs) converged toward gene networks involved in similar biological functions. Weighted gene co-expression analysis generated 54 unique modules of interconnected gene hubs, two of which included a combination of all experimental groups and were significantly enriched in DEGs, whose function was consistent with that predicted in the RRHO GO analysis. This multimodel approach showed transcriptional synchrony between models of stress with hormonal, environmental or genetic construct validity shedding light on common genomic drivers that embody the multifaceted nature of stress-related disorders.

neuroscience↗

bioRxiv2020

The evolution of trait variance creates a tension between species diversity and functional diversity

It seems intuitive that species diversity promotes functional diversity. For example, more plant species imply more diverse leaf chemistry and thus more kinds of food for herbivores. Here we argue that the evolution of functional trait variance challenges this view. We show that trait-based eco-evolutionary processes force species to evolve narrower trait breadths in tightly packed communities, in their effort to avoid competition with neighboring species. This effect is so strong as to reduce overall trait space coverage, overhauling the expected positive relationship between species- and functional diversity. Empirical data from Galápagos land snail communities proved consistent with this claim. As a consequence, trait data from species-poor communities may misjudge functional diversity in species-rich ones, and vice versa.Competing Interest StatementThe authors have declared no competing interest.View Full Text

ecology↗

bioRxiv2020

A unified model of species abundance, genetic diversity, and functional diversity revealsthe mechanisms structuring ecological communities

Biodiversity accumulates hierarchically by means of ecological and evolutionary processes and feedbacks. Reconciling the relative importance of these processes is hindered by current theory, which tends to focus on a single spatial, temporal or taxonomic scale. We introduce a mechanistic model of community assembly, rooted in classic island biogeography theory, which makes temporally explicit joint predictions across three biodiversity data axes: i) species richness and abundances; ii) population genetic diversities; and iii) trait variation in a phylogenetic context. We demonstrate that each data axis captures information at different timescales, and that integrating these axes enables discriminating among previously unidentifiable community assembly models. We combine our massive eco-evolutionary synthesis simulations (MESS) with supervised machine learning to fit the parameters of the model to real data and infer processes underlying how biodiversity accumulates, using communities of tropical trees, arthropods, and gastropods as case studies that span a range of spatial scales.

evolutionary biology↗

bioRxiv2019

The LTB4-BLT1 signaling axis coordinates actomyosin dynamics and β-2 Integrin trafficking to drive intravascular neutrophil response to infection

The eicosanoid Leukotriene B4 (LTB4) relays chemotactic signals to direct neutrophil migration to inflamed sites through its receptor BLT1. However, the mechanisms by which the LTB4-BLT1 axis relays chemotactic signals during intravascular neutrophil response to inflammation remain unclear. Here, we report that LTB4 produced by neutrophils acts as an autocrine/paracrine signal to direct the vascular recruitment, arrest and extravasation of neutrophils in a sterile inflammation model in the mouse footpad. Using Intravital Subcellular Microscopy (ISMic), we reveal that LTB4 elicits sustained cell polarization and adhesion responses during neutrophil arrest in vivo. Specifically, LTB4 signaling coordinates the dynamic redistribution of non-muscle Myosin IIA (NMIIA) and {beta}2-integrin (Itgb2), which facilitate neutrophil arrest and extravasation. Notably, we also found that neutrophils shed extracellular vesicles (EVs) in the vascular lumen, and that inhibition of EV release blocks LTB4-mediated autocrine/paracrine signaling required for neutrophil arrest and extravasation. Overall, we uncover a novel complementary mechanism by which LTB4 relays extravasation signals in neutrophils during early inflammation response. SUMMARYNeutrophils arrest and extravasate from the blood vessels in response to infection and injury. Using intravital subcellular microscopy, Subramanian et al. identify a role for extracellular vesicles-based autocrine/paracrine LTB4-BLT1 signaling in promoting the re-arrangement of actomyosin cytoskeleton and {beta}2-integrin during neutrophil extravasation in live animals.

cell biology↗