Biology subjects

Caillon, A.

Publications and source records attributed to Caillon, A..

5 recordsLinked to original sources

bioRxiv2026

Inhibition of macrophage neuraminidase 1 protects against immune thrombocytopenia by limiting platelet clearance

Immune thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by a reduction in circulating platelet levels, primarily due to generation of autoantibodies to platelet surface antigens followed by their spleen macrophage-mediated clearance. Emerging evidence implicates neuraminidase (sialidase) enzymes including neuraminidase 1 (NEU1) in platelet clearance and ITP severity; however, the underlying cellular mechanisms remain unknown. Using tissue-specific NEU1 knockout mouse models, we studied the contribution of platelet and macrophage NEU1 to ITP pathogenesis and evaluated whether pharmacological inhibition of NEU1 could preserve platelet counts in a murine ITP model. Constitutive and macrophage-specific, but not platelet-specific, NEU1 knockout mice showed a protection against reduction of platelet counts in the passive ITP model suggesting that macrophage, but not platelet, NEU1 promotes platelet clearance. Genetic deletion or pharmacological blockade of macrophage NEU1 also reduced platelet phagocytosis by cultured macrophages in vitro. The selective NEU1 inhibitor CG33301 protected mice against anti-CD41a antibody-induced thrombocytopenia and showed a higher efficacy compared to pan neuraminidase inhibitor oseltamivir phosphate. Our results demonstrate that the macrophage pool of NEU1 plays a central role in platelet clearance by splenocytes during ITP by activating their phagocytosis and suggest that selective NEU1 inhibition may be a promising therapeutic strategy for this disease.

biochemistry↗

bioRxiv2026

Early metabolic reprogramming licenses Streptococcus pneumoniae for Influenza-driven superinfection

Bacterial pneumonia remains a major cause of morbidity and mortality following influenza A virus (IAV) infection. However, the adaptive mechanisms that enable pathogen expansion in the post-viral lung remain poorly defined. Here, using a mouse model of IAV-Streptococcus pneumoniae superinfection, we characterize bacterial transcriptional reprogramming in vivo. We identify alcohol dehydrogenases (AdhA and AdhE), that support NAD regeneration during mixed-acid fermentation, as key determinants of bacterial fitness specifically in the IAV-primed lung. Genetic deletion of these results in a pronounced fitness defect during superinfection but not in primary bacterial pneumonia. Consistent with this requirement, pharmacological inhibition of alcohol dehydrogenases limits bacterial expansion and dissemination following IAV infection. Mechanistically, we show that IAV infection profoundly remodels the lung environment, inducing hypoxia and increasing the availability of alternative carbon sources, which together impose a metabolic dependency on Adh for bacterial expansion. Our findings place metabolic adaptation as a central driver of pneumococcal outgrowth following viral infection and reveal exploitable vulnerabilities for therapeutic intervention.

microbiology↗

bioRxiv2026

A Glycosylation-Dependent Checkpoint Restrains Intestinal Intra-Epithelial Lymphocyte Activation

Intraepithelial lymphocytes (IELs) are abundant in the intestinal epithelium, where they maintain barrier integrity and provide immune defense. Because of their potent cytotoxic and effector potential, IEL activity must be tightly controlled to prevent tissue damage. However, the mechanisms that calibrate IEL responsiveness remain unclear. Here, we identify glucosaminyl (N-acetyl) transferase 2 (Gcnt2) as a key restrainer of both natural and induced gut IEL. Among T cells, Gcnt2 is uniquely enriched in the intestine and partly dependent on retinoic acid signaling. GCNT2-mediated branched glycosylation marks IELs with signatures of tissue adaptation and reduced TCR responsiveness. Genetic ablation of Gcnt2 enhanced IEL degranulation, cytokine production, and cytotoxicity upon stimulation, improving bacterial clearance and limiting infection-induced disease, while aggravating the pathological consequences of strong T cell activation. Mechanistically, GCNT2-mediated glycosylation of CD45 reduced its phosphatase activity, thereby dampening TCR signaling and effector responses. Together, these findings reveal GCNT2 as a glycosylation-dependent checkpoint that fine-tunes IEL effector functions, uncovering a novel mechanism by which the intestinal immune system balances responsiveness and tolerance. SummaryGCNT2-mediated I-branching glycosylation of CD45 restrains IEL activation.

immunology↗

bioRxiv2024

Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC.

Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme uncapable of free diffusion between the cells and their cross-correction which limits development of therapies based on the enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied by behaviour test battery staring from the age of 6 months. At the age of [~]8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage and other biomarkers of the disease. We found that the treatment corrected several behaviour deficits including hyperactivity and reduction of socialization, but not a memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1{beta}, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with the cells from normal healthy donor. They also suggest, that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.

genetics↗

bioRxiv2022

A cellular assay for spike/ACE2 fusion: quantification of fusion-inhibitory antibodies after COVID-19 and vaccination

Not all antibodies against SARS-CoV-2 inhibit viral entry and hence infection. Neutralizing antibodies are more likely to reflect real immunity, however certain of these tests investigate protein/protein interaction rather than the fusion event. Viral and pseudoviral entry assays detect functionally active antibodies, however they are cumbersome and burdened by biosafety and standardization issues. We have developed a Spike/ACE2-dependant cell-to-cell fusion assay, based on a split luciferase. Hela cells stably transduced with Spike and a large fragment of luciferase were co-cultured with Hela cells transduced with ACE2 and the complementary small fragment of luciferase. Within 24h, cell fusion occured allowing the measurement of luminescence. Light emission was abolished in the absence of Spike and reduced in the presence of an inhibitor of Spike-processing proteases. Serum samples from COVID-19-negative, non-vaccinated individuals, or sera from patients at the moment of first symptoms did not lead to a significant reduction of fusion. In contrast, sera from COVID-19-positive patients as well as sera from vaccinated individuals reduced the fusion. In conclusion, we report a new method measuring fusion-inhibitory antibodies in serum, combining the advantage of a functional full Spike/ACE2 interaction with a high degree of standardization, easily allowing automation in a standard bio-safety environment.

microbiology↗