Biology subjects

Massaro, M.

Publications and source records attributed to Massaro, M..

5 recordsLinked to original sources

bioRxiv2026

An Altered Glycome Shapes IgA B-Cell Responses and Gut Immunity During Intestinal Inflammation

A healthy gut immune system balances pathogen defense and tolerance to beneficial microbes. This equilibrium is sustained by coordinated mechanisms where B cells (BCs) play a central role, and secretory immunoglobulin A (SIgA) regulates microbiome composition. In ulcerative colitis (UC), impaired tolerogenic pathways result in exaggerated immune activation, epithelial dysfunction, and tissue damage; however, the contribution of BCs to disease pathogenesis remains unclear. Notably, sialylation is crucial to B-cell function, but its relevance in the intestinal IgA B-cell response has been scarcely explored. Here, we show that SIgA from active UC patients displays an inflammation-dependent reduction in (2,6)-sialylation. This desiaylation is recapitulated in dextran sodium sulfate-induced colitis, where IgA plasma cells (IgA+ PCs) and BCs exhibit a similar glycophenotype. Functional analyses reveal that BCs lacking (2,6)-sialylation on N-glycans exhibit defective differentiation into IgA PCs and diminished capacity to suppress intestinal inflammation in vivo, with increased neutrophil infiltration. Moreover, transcriptomic analyses of UC patient samples suggest a synergistic contribution of neuraminidase activity and reduced bioavailability of sialic acid precursors, leading to SIgA desialylation. Collectively, these findings uncover a glycosylation-dependent pathological circuit in which altered sialylation of SIgA and BCs disrupts their function, compromising mucosal homeostasis in intestinal inflammation.

immunology↗

bioRxiv2026

Multi-dimensional optimization of a lysin towards a ribolysin against life-threatening S. aureus infections: Fc-LysM-CHAP and its strong synergy with standard of care antibiotics

Bacterial lysins are promising novel antimicrobials but are limited by poor pharmacokinetics and challenging manufacturability. We developed a lysin discovery platform tailored for lysin delivery via mRNA: staphylococcal LysM-CHAP (cysteine, histidine-dependent amidohydrolases/peptidase) autolysin was selected and its serum half-life extended via Immunoglobulin G1-Fc-fusion. The Fc-induced drop in lysin potency was rescued by the concerted optimization of linkers, binding kinetics and catalytic activity, using a combination of rational and AI-guided approaches. The engineered Fc-LysM-CHAP was active against planktonic bacteria (minimum inhibitory concentration of 1 - 2 {micro}g/mL) and simulated endocardial vegetations and synergized strongly (Fractional eradication concentration index FECI = 0.06) with cell wall active antibiotics in vitro. In mouse models of Staphylococcus aureus sepsis, the recombinant Fc-LysM-CHAP - antibiotic combination was superior to single agent treatments and mRNA-delivered Fc-LysM-CHAP showed single agent activity at a mRNA-lipid nanoparticle dose as low as 0.2 mg/kg.

microbiology↗

bioRxiv2026

Enhanced intercellular transfer of mitochondria from nuclear respiratory factor 1 (NRF1)-primed mesenchymal stem cells: towards creation of superior mitochondrial delivery hubs

Mitochondrial dysfunction is a pervasive hallmark of diverse diseases. In endothelial cells (ECs), oxidative stress, bioenergetic failure, and dysregulated mitochondrial dynamics (fusion-fission, mitophagy) damage the endothelium and promote vascular pathologies such as diabetes, atherosclerosis, and aging. Mitochondrial augmentation, via direct transplantation of isolated mitochondria or cell-to-cell transfer of the organelle, has emerged as a strategy to restore mitochondrial function in metabolically compromised cells. We recently established that overexpressing nuclear respiratory factor 1 (NRF1), a driver of mitochondrial biogenesis, in mesenchymal stem cells (MSCs) increases mitochondrial content and preserves mitochondrial function under senescence-inducing stress. Here, we advance NRF1-primed MSCs as enhanced mitochondrial hubs for intercellular mitochondrial delivery to cells undergoing mitochondrial dysfunction. We hypothesized that NRF1 overexpression engages mitochondrial transfer machinery, thereby enhancing both tunneling nanotube (TNT)- and extracellular vesicle (EV)-mediated mitochondrial transfer to stressed ECs, improving EC mitochondrial fitness and health. mRNA-mediated NRF1 priming of MSCs increased expression of proteins involved in mitochondrial motility and transfer, enhanced TNT formation, and increased production of mitochondria-containing EVs. Single-cell RNA sequencing (scRNA-seq) results show that NRF1 priming shifted MSCs into distinct transcriptional states, with NRF1-enriched clusters exhibiting coordinated upregulation of cell-adhesion/cytoskeletal connectivity programs and vesicle-fusion/trafficking pathways, features consistent with enhanced structural coupling and secretory transfer capacity. NRF1 priming increased TNT-like F-actin intercellular bridges in direct co-culture and elevated mitochondria-containing EV transfer in transwell assays, demonstrating augmented mitochondrial delivery through both contact-dependent and contact-independent routes. Consequently, recipient ECs displayed reduced mitochondrial ROS, preserved membrane potential, improved oxidative phosphorylation and ATP production, rebalanced mitochondrial dynamics of fusion-fission and mitophagy. NRF1-primed MSCs further attenuated oxidative stress-induced EC senescence and apoptosis. Together, these findings identify NRF1 activation as a mechanism to reprogram MSCs into high-capacity mitochondrial donors and support NRF1-driven mitochondrial hub engineering as a strategy to strengthen mitochondrial transfer-based therapies for diseases characterized by mitochondrial dysfunction.

bioengineering↗

bioRxiv2023

Candidate gene length polymorphisms are linked to dispersive behaviour: searching for a mechanism behind the "paradox of the great speciators"

The "paradox of the great speciators" has puzzled evolutionary biologists for over half a century. A great speciator requires excellent dispersal ability to explain its occurrence on multiple islands, but reduced dispersal ability to explain its high number of subspecies. A rapid reduction in dispersal ability is often invoked to solve this apparent paradox, but a proximate mechanism has not been identified. Here, we explore the role of six genes linked to migration and animal personality differences (CREB1, CLOCK, ADCYAP1, NPAS2, DRD4, and SERT) in 20 South Pacific populations of silvereye (Zosterops lateralis) that range from highly sedentary to partially migratory, to determine if genetic variation is associated with dispersal propensity. We detected genetic associations in three of the six genes: i) in a partial migrant population, migrant individuals had longer microsatellite alleles at the CLOCK gene compared to resident individuals from the same population; ii) CREB1 displayed longer average microsatellite allele lengths in recently colonised island populations (< 200 years), compared to evolutionarily older populations. Bayesian broken stick regression models supported a reduction in CREB1 length with time since colonisation and decreasing dispersal propensity; and iii) like CREB1, DRD4 showed differences in polymorphisms between recent and old colonisations but a further sample size is needed to confirm. ADCYAP1, SERT, and NPAS2 were variable but that variation was not associated with dispersal propensity. The association of genetic variants at three genes with migration and dispersal ability in silvereyes provides the impetus for further exploration of genetic mechanisms underlying dispersal shifts, and the prospect of resolving a long-running evolutionary paradox through a genetic lens.

evolutionary biology↗

bioRxiv2020

Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition.

1.Immune evasion is a hallmark of persistent echinococcal infection, comprising modulation of innate immune cells and antigen-specific T cell responses. However, recognition of Echinococcus granulosus by dendritic cells (DCs) is a key determinant of the hosts response to this parasite. Given that mTOR signaling pathway has been described as a regulator linking metabolism and immune function in DCs, we reported for the first time in these cells, global translation levels, antigen uptake, phenotype, cytokine transcriptional levels, and splenocyte priming activity upon recognition of the hydatid fluid (HF) and the highly glycosylated laminar layer (LL). We found that LL induced a slight up-regulation of CD86 and MHC II in DCs and also stimulated the production of IL-6 and TNF-. By contrast, HF did not increase the expression of any co-stimulatory molecules, but also down-modulated CD40 and stimulated the expression of the anti-inflammatory cytokine IL-10. Both parasitic antigens promoted protein synthesis through mTOR activation. The use of rapamycin decreased the expression of the cytokines tested, empowered the down-modulation of CD40 and also reduced splenocyte proliferation. Finally, we showed that E. granulosus antigens increase the amounts of LC3-positive structures in DCs which play critical roles in the presentation of these antigens to T cells.

immunology↗