Biology subjects

Seveau, S.

Publications and source records attributed to Seveau, S..

4 recordsLinked to original sources

bioRxiv2026

Gelsolin protects mitochondria and regulates inflammation during Legionella pneumophila infection

Legionella pneumophila (L. pneumophila) is the causative agent of Legionnaires' disease, a severe bacterial pneumonia. Difficulty in diagnosing Legionnaires' disease leads to an underreporting of cases and delayed treatment. Rapid-acting, broad-spectrum therapies are needed to treat pathology while avoiding antibiotic resistance. We showed that gelsolin knockout (gsn-/-) mice succumb more quickly to severe L. pneumophila infection despite no difference in bacterial loads in the lung compared to wild type mice. There is an increase in CXCL1/KC production from macrophages from gsn-/- mice, which is accompanied by increased neutrophils and apoptosis in their lungs. Neutrophils lacking gelsolin produce fewer neutrophil extracellular traps, and their mitochondrial capacity is diminished in response to L. pneumophila. Gelsolin is required for maintaining mitochondrial network morphology and respiration in L. pneumophila infected macrophages. When given recombinant gelsolin protein, gsn-/- mice survive significantly longer during severe L. pneumophila infection, with reduced lung pathology, and the inflammatory signature of their macrophages was reduced in vitro. Together, gelsolin protects mice during severe L. pneumophila infection, dampens inflammation, promotes mitochondrial health, and maintains neutrophil function.

immunology↗

bioRxiv2026

Age Dependent Immunopathology Drives Pneumonia-Associated Cardiac Dysfunction During Streptococcus pneumoniae Infection

Aging is a major risk factor for severe Streptococcus pneumoniae (Spn) infection and pneumonia-associated - major adverse cardiac events (PA-MACE), yet underlying mechanisms remain unclear. Using young and aged murine models, we show that aging exacerbates bacterial burden, mortality, and cardiac dysfunction following Spn infection, associated with impaired macrophage bacterial killing. Single-cell RNA sequencing infected hearts revealed extensive age-dependent remodeling across immune and stromal compartments. Aged mice exhibited heightened pro-inflammatory myeloid responses, with increased neutrophil infiltration characterized by elevated S100A8/9 and LCN2 and reduced antimicrobial programs. Macrophages displayed defective efferocytosis, including disruption of the GAS6-AXL axis. Aging also drove expansion of an infection-responsive fibroblast population with inflammatory signatures and reduced extracellular matrix gene expression. These changes were linked to oxidative stress and impaired glucose oxidation. Notably, anti-inflammatory treatment rescued cardiac dysfunction, implicating excessive inflammation as a central driver of PA-MACE. Together, these findings define mechanisms linking aging to pneumococcal cardiac complications and identify potential therapeutic targets.

immunology↗

bioRxiv2025

AI-based decoding of long covid cognitive impairments in mice using automated behavioral system and comparative transcriptomic analysis

Long COVID (LC) following SARS-CoV-2 infection affects millions of individuals world-wide and manifests with a variety of symptoms including cognitive dysfunction also known as "brain fog". This is characterized by difficulties in executive functions, planning, decision-making, working memory, impairments in complex attention, loss of ability to learn new skills and perform sophisticated brain tasks. No effective treatment options currently exist for LC-related cognitive dysfunction. Here, we use the IntelliCage, which is an automated tracking system of cognitive functions, following SARS-CoV-2 infection in mice, measuring the ability of each mouse within a group to perform tasks that mimic complex human behaviors, such as planning, decision-making, cognitive flexibility, and working memory. Artificial intelligence and machine learning analyses of the tracking data classified LC mice into distinct behavioral categories from non-infected control mice, permitting precise identification and quantification of complex cognitive dysfunction in a controlled, replicable manner. Importantly, we find that brains from LC mice with cognitive dysfunction exhibit transcriptomic alterations similar to those observed in humans suffering from LC-related cognitive impairments, including altered expression of genes involved in learning, executive functions, synaptic functions, neurotransmitters and memory. Together, our findings establish a validated murine model and an automated unbiased approach to study LC-related cognitive dysfunction for the first time, and providing a valuable tool for screening potential treatments and therapeutic interventions.

neuroscience↗

bioRxiv2021

Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and thrombosis

SARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed 1. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated in SARS-CoV-2 infections, and that CASP4 expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infected Casp11-/- mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) and gasdermin-D knock out (Gsdmd-/-) mice. GSDMD is a downstream effector of CASP11 and CASP1. Notably, viral titers were similar in the three genotypes. Global transcriptomics of SARS-CoV-2-infected WT, Casp11-/- and Gsdmd-/- lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11-/- mice. We confirmed that protein levels of inflammatory mediators IL-1{beta}, IL6, and CXCL1, and neutrophil functions, were reduced in Casp11-/- lungs. Additionally, Casp11-/- lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.

immunology↗