Biology subjects

Saraiva, M.

Publications and source records attributed to Saraiva, M..

7 recordsLinked to original sources

bioRxiv2026

A pan-cancer single-cell atlas of pericytes

Pericytes display marked tissue-specific transcriptional identities, raising the question of whether tumour-associated pericytes converge towards shared adaptive states across cancers. Here, we built a pan-cancer single-cell RNA sequencing atlas of pericytes, integrating nearly four million cells across nine tissues, complemented by spatial transcriptomic analyses. Despite their physiological diversity, pericytes were recurrently expanded in tumours and converged on a common transcriptional program, the tumour-associated pericyte signature (TAPS). TAPS robustly identified pericytes across datasets, outperforming canonical markers in tumour contexts. Tumour-associated pericytes further diversified into specialised states including extracellular matrix (ECM)-associated and interferon (IFN)-responsive programs, which occupy mutually exclusive tumour ecosystems. ECM-associated pericytes were enriched in desmoplastic, fibroblast-rich regions and were associated with adverse clinical outcomes across multiple cancer types. IFN-responsive pericytes accumulated in inflammatory niches, with macrophages implicated as candidate drivers of specialisation. Together, our multi-layered analysis defines convergent and specialised tumour-associated pericyte programs across human cancers.

cancer biology↗

bioRxiv2026

Cytolethal distending toxin promotes epithelial-to-mesenchymal transition by modulating AKT-Dependent β-catenin Ser552 phosphorylation

Bacterial genotoxins, Cytolethal Distending Toxin (CDT) and colibactin, cause DNA damage in intoxicated epithelial cells of the host. DNA damage influences {beta}-catenin signaling, altering its stability and nuclear translocation, potentially contributing to cancer development. Using non-transformed hepatocytes and cancer-derived intestinal and hepatic epithelial cell lines, we showed that CDT/CdtB induces the phosphorylation of {beta}-catenin at serine 552, along with the loss of {beta}-catenin from adherens junctions. This leads to the subsequent cytoplasmic accumulation and nuclear translocation of {beta}-catenin, ultimately driving TCF/LEF transcription, the crucial downstream event of Wnt/{beta}-catenin signaling, as well as the transcription of some {beta}-catenin target genes. Colibactin induces similar effects. MK-2206, a direct AKT inhibitor, and metformin, an AMP-activated protein kinase activator that indirectly inhibits AKT, both protected cells against various effects induced by CdtB exposure. These effects include {beta}-catenin phosphorylation at Ser552, the disassembly of cell-cell junctions and the subsequent nuclear accumulation of phosphorylated {beta}-catenin, leading to reduced TCF/LEF-mediated transcription. Additionally, MK-2206 and metformin protected from CdtB-induced epithelial-mesenchymal transition (EMT), including increased nuclear accumulation of SNAIL, enhanced matrix degradation and motility. Overall, these data show that infection with genotoxin-producing bacteria controls some EMT features through {beta}-catenin and AKT-dependent signaling.

cancer biology↗

bioRxiv2025

Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy

The immune response to Mycobacterium tuberculosis is accompanied by metabolic adaptations that fuel host immunity, but that are exploited by the pathogen to ensure persistence and growth. Nuclear receptors, such as liver-X-receptors (LXR), orchestrate macrophage immunometabolic adaptations to infection and globally associate with tuberculosis (TB) protection. Here, we show that the "signalling by nuclear receptors" (SNR) pathway is detected in the whole blood of TB patients and that its expression correlates with disease severity. Accordingly, we also show that the activation of the LXR pathway progressively increases in the lungs of M. tuberculosis-infected C57BL/6 and C3HeB/FeJ mice. Pharmacologic activation of LXR, specifically at the chronic stage of infection, improved infection outcomes and significantly prolonged the survival of the highly susceptible C3HeB/FeJ mice. Common to both mouse models and to in vitro macrophage infections, LXR activation enhanced bacterial control together with an increase in extracellular cholesterol levels. We propose that progressive LXR activation is required to fine-tune host cholesterol availability during M. tuberculosis infections and restrict access to this nutrient during chronic stages of infections. Collectively, we identify the SNR pathway as a potential biomarker of TB severity and timely LXR activation as a candidate host-directed therapy.

immunology↗

bioRxiv2024

Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring

The natural diversity of Mycobacterium tuberculosis is gaining relevance in dictating the outcome of tuberculosis (TB). We previously revealed a link between TB severity and M. tuberculosis-driven evasion of the macrophage cytosolic surveillance systems, with isolates from severe TB cases reducing inflammasome activation and interleukin (IL)-1{beta} production by infected cells. IL-1{beta} production and inflammasome activation are commonly associated with the metabolic reprogramming of stimulated macrophages. Thus, we questioned whether the differential modulation of the inflammasome and IL-1{beta} by M. tuberculosis isolates depended on distinct macrophage metabolic reprogramming. Using metabolic inhibitors, mice deficient for key metabolic regulators, and a metabolomics approach, we found that the macrophage metabolic landscape was similar regardless of the infecting M. tuberculosis isolate. Paralleling single-TLR activated macrophages, inhibition of glycolysis during infection impaired IL-1{beta} secretion. However, departing from TLR based models, in M. tuberculosis-infected macrophages IL-1{beta} secretion was independent of macrophage mitochondrial metabolic changes and the transcription factor hypoxia-inducible factor (HIF)-1. Additionally, we found a previously unappreciated impact of host metabolic inhibitors on the pathogen, and show that inhibition of the mycobacteria metabolism dampened both inflammasome activation and IL-1{beta} production. Collectively, our study raises awareness of the potential confounding effect of host metabolic inhibitors acting on the pathogen itself and demonstrates that the modulation of the inflammasome by M. tuberculosis may be uncoupled from the host metabolic reprogramming. Author SummaryMycobacterium tuberculosis is the causative agent of tuberculosis and one of the top infectious killers in the world, with around 1.3 million deaths reported annually. The genetic variability of this pathogen can shape its interaction with the host and modulate disease outcomes. We previously found that M. tuberculosis clinical isolates from patients with severe forms of tuberculosis evade cytosolic surveillance systems in macrophages. Here, we explored whether this evasion tactic was linked to metabolic alterations in the infected macrophages. We found that different M. tuberculosis isolates induced similar metabolic changes in infected macrophages. Additionally, we demonstrate that both host glycolysis and pathogens metabolism were pivotal for maximum IL-1{beta} production. These findings highlight the complexity of macrophage-pathogen interactions and emphasize that bacterial metabolism should be considered in metabolic studies and may be amenable to therapeutic intervention against tuberculosis.

immunology↗

bioRxiv2023

A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations

Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to the transformation of a capillary into a shunt remain unclear and how shunts can be reverted into capillaries is poorly understood. Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in endothelial cell (EC) volume of venous origin (hypertrophic venous cells) are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signaling cell-autonomously regulates EC volume, demonstrating that our discoveries link with hereditary hemorrhagic telangiectasia (HHT)-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. We demonstrate that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocates for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.

cell biology↗

bioRxiv2022

Serum Amyloid A proteins reduce bone mass during mycobacterial infections

Osteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required. Using genetically engineered mice and morphometric, transcriptomic and functional analyses, we found that infection with Mycobacterium avium impacts bone turnover by decreasing bone formation and increasing bone resorption, in a IFNg- and TNFa-dependent manner. IFNg produced during infection enhanced macrophage TNFa secretion, which in turn increased the production of serum amyloid A (SAA) 3. Saa3 expression was upregulated in the bone of both M. avium- and Mycobacterium tuberculosis-infected mice and SAA proteins were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine network operating in macrophages and bone homeostasis and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.

immunology↗

bioRxiv2018

Mycobacteria recycle their peptidoglycan via a novel pathway which influences antimicrobial resistance and limits proliferation in macrophages.

Growth and division by most bacteria requires remodeling and cleavage of their cell wall. A byproduct of this process is the generation of free peptidoglycan (PG) fragments known as muropeptides. These muropeptides are recycled in many model organisms, where the bacteria can harness their unique nature as a signal for cell wall damage. These molecules also serve as important signals for hosts where binding to specific receptors reports on the presence of intracellular bacteria. Despite this critical role for muropeptides, it has long been thought that pathogenic mycobacteria such as Mycobacterium tuberculosis do not recycle their PG. Herein we show for the first time that M. tuberculosis and Mycobacterium bovis BCG are able to recycle components of their PG. We demonstrate that the core-mycobacterial gene lpqI, encodes an authentic NagZ {beta}-N-acetylglucosaminidase and that it is essential for PG-derived amino sugar recycling via an unusual pathway. By characterizing an M. bovis BCG strain lacking lpqI we are also able to show that stem-peptide recycling proceeds independent of amino sugar recovery and loss of lpqI leads to antimicrobial resistance in vitro. Together these data provide a critical first step in understanding how mycobacteria recycle their peptidoglycan.

microbiology↗