Biology subjects

Dumas, A.

Publications and source records attributed to Dumas, A..

5 recordsLinked to original sources

bioRxiv2026

The lysosomal glutamine transporter SLC38A7/SNAT7 modulates SAMHD1 antiviral activity and promotes HIV-1 production in human macrophages

HIV-1 (Human Immunodeficiency Virus type 1) infects macrophages, which resist to the cytopathic effects of the virus and are considered as viral reservoirs. However, the cellular factors involved in viral production by human macrophages have not been fully identified. In this study, we focused on the amino acid transporter SNAT7 (small neutral amino-acid transporter 7), member of the SLC38 solute carrier family, which is the main lysosomal transporter of glutamine from the lysosome to the cytoplasm. Its expression was increased by HIV-1 infection. We revealed that the absence of SNAT7 inhibited viral production not only at the level of protein synthesis, but also early at the level of reverse transcription, without affecting global RNA or protein synthesis in the cells. The reduction in HIV expression upon SNAT7 depletion correlated with a reduction in the levels of an inactive form of the SAMHD1 (SAM domain- and HD domain-containing protein) restriction factor and was rescued following SAMHD1 degradation. Lastly, supplementation of the extracellular medium with glutamine in the absence of SNAT7 partially restored viral production. Together, our data reveal that glutamine extracted from lysosomes is involved in the early stages of the HIV-1 cycle and that the SNAT7 glutamine transporter acts as a dependency factor for HIV-1 in human macrophages.

microbiology↗

bioRxiv2025

The unique lipopolysaccharide composition of Salmonella Typhimurium ST313 dampens pyroptosis and inflammasome activation and suppresses host cell death

In humans, non-typhoidal Salmonella (NTS) serovars, such as Salmonella enterica Typhimurium cause self-limiting gastroenteritis. However, invasive non-typhoidal Salmonella (iNTS) isolates ST313 have emerged in sub-Saharan Africa that cause a severe bacteremia in immunocompromised individuals including HIV-positive adults. Despite a decade of studies comparing ST313 to the classical diarrheal S. Typhimurium ST19 pathovariant, the molecular basis of the differences of pathogenesis between these bacteria remains unclear. Here we used primary human macrophages infected with the invasive S. Typhimurium ST313 D23580 isolate and the reference ST19 4/74 isolate as an in vitro model of infection. Transcriptomic profiling revealed that primary human macrophages infected with ST313 bacteria had distinct patterns of host cell death and inflammation responses compared to ST19-infected cells. Specifically, infection with ST313 isolate induced significantly less pyroptotic cell death which was associated with minimal processing of Gasdermin-D. We discovered that S. Typhimurium ST313 stimulated reduced IL-1{beta} release and a low-level activation of the upstream inflammasome signaling cascade with reduced Caspase-4 and Caspase-1 cleavage. To investigate the molecular basis of this phenotype we purified lipopolysaccharide (LPS) species from ST313 to identify physical properties and structures that were distinct from ST19 LPS. The ST313-derived LPS was less pro- inflammatory than LPS from ST19, mirroring the low inflammatory phenotype of the live bacteria. Together, our data reveal that the unique LPS of ST313 is responsible for the reduced level of pyroptosis in human macrophages. This phenotype is consistent with the intracellular persistence and dissemination of these pathogenic bacteria. AUTHOR SUMMARYNon-typhoidal Salmonella (NTS) is a foodborne microbial pathogen that causes a self- limiting gastroenteritis in humans. However, in recent decades invasive non-typhoidal Salmonella (iNTS) isolates have emerged in sub-Saharan Africa, and are currently causing severe bloodstream infections responsible for about 66,000 deaths each year, largely in immunocompromised individuals. To investigate differences in pathogenicity between iNTS and NTS strains, we studied the infection of primary human macrophage with an iNTS ST313 isolate from Malawi in comparison to a gastroenteritis-associated ST19 reference strain. Primary macrophages play a key role in clearing Salmonella infections by recognizing bacterial components such as lipopolysaccharide (LPS). LPS induces immune responses including activation of cytokine release, inflammation and host cell death for effective bacterial elimination. Our study revealed that the iNTS isolate survived better in human primary macrophages than the NTS strain due to reduced inflammatory cell death, weakened inflammasome activation and lower cytokine release. We suggest that the distinct LPS structure is responsible for these dampened immune responses which aid the spread and persistence of S. Typhimurium ST313 in the human host.

microbiology↗

bioRxiv2025

An extracellular complex between CLE-1/collagen XV/XVIII and Punctin/MADD-4 defines cholinergic synapse identity

The precise localization of postsynaptic receptors opposite neurotransmitter release sites is essential for synaptic function. This alignment relies on adhesion molecules, intracellular scaffolds, and a growing class of extracellular scaffolding proteins. However, how these secreted proteins are retained at synapses remains unclear. We addressed this question using C. elegans neuromuscular junctions, where Punctin, a conserved extracellular synaptic organizer, positions postsynaptic receptors. We identified CLE-1, the ortholog of collagens XV/XVIII, as a key stabilizer of Punctin. Punctin and CLE-1B, the main isoform present at neuromuscular junctions, form a complex and rely on each other for synaptic localization. Punctin undergoes cleavage, and in the absence of CLE-1, specific fragments are lost, resulting in the mislocalization of cholinergic receptors to GABAergic synapses. Additionally, CLE-1 regulates receptor levels independently of Punctin. These findings highlight a crucial extracellular complex that maintains synapse identity.

neuroscience↗

bioRxiv2022

A Translational Tissue Engineering Approach to Airway Reconstruction Leveraging Decellularized Meniscus and Cartilage Progenitor Cells

Severe subglottic stenosis develops in over 20,000 infants per year and requires laryngotracheal reconstruction (LTR) to enlarge the airway by implanting autologous cartilage from a rib graft. However, young children often lack sufficiently sized costal cartilage resulting in increased donor site morbidity and operative time, as well as an elevated risk for airway restenosis necessitating revision surgery. To overcome these limitations, we have created a first-of-its-kind scaffold based on porcine meniscal cartilage decellularization (MEND) by selectively digesting the elastin and blood vessels uniquely present in the meniscus to create microchannels that support cellular re-invasion. Here we demonstrated that MEND can be fully recellularized in 3 days with ear-derived cartilage progenitor cells (eCPCs) and reaches structural and functional maturation suitable for implant within 3 weeks of chondrogenic differentiation, a time frame compatible with clinical translation, a first in airway tissue engineering. To further this therapy toward clinical translation, we validated the eCPCs-MEND grafts in a New Zealand white rabbit LTR model. Our results demonstrated airway expansion, graft re-epitheliazation, neocartilage formation, and integration with adjacent native laryngotracheal cartilage, notably at a higher degree than the standard of care of autologous costal cartilage. No instances of adverse events of extrusion, granulation, infection, or calcification were observed in any of the 38 rabbits of our 3 months study. These results demonstrate the feasibility of our translational tissue engineering approach to laryngotracheal reconstruction and could overcome the autograft-associated limitations in pediatric patients and a decrease the risk of invasive revision surgery.

bioengineering↗

bioRxiv2018

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

neuroscience↗