Biology subjects

Carlos, A. R.

Publications and source records attributed to Carlos, A. R..

4 recordsLinked to original sources

bioRxiv2026

CD24 Acts as an Evolutionarily Conserved Innate Immune Checkpoint in Colorectal Cancer

Checkpoint immunotherapy has transformed cancer treatment, yet current approaches targeting adaptive immunity benefit only a subset of patients, leaving innate immunity as a largely untapped therapeutic frontier. Here, we identify CD24 as an innate immune checkpoint that protects colorectal tumors from macrophage-mediated clearance through an evolutionarily conserved recognition mechanism. Using zebrafish xenografts of isogenic colorectal cancer (CRC) cell lines, SW480 and SW620, we show that high CD24 expression in SW620 correlates with an immune-evasive, macrophage-resistant phenotype. Loss of human CD24 dramatically sensitizes tumors to clearance in zebrafish, while pharmacological macrophage depletion abolishes this effect. Mechanistically, CD24 suppresses innate immunity in a multilayered fashion, by limiting myeloid recruitment, dampening TNF-driven macrophage inflammatory polarization, and blocking phagocytosis. Live imaging further revealed that CD24 constrains macrophages to a restrained, patrol-like state, and that its loss enables them to adopt a highly motile, tumor-directed, and functionally engaged state, characterized by increased fusion activity and myeloid intercellular interactions. We show that zebrafish macrophages respond to human CD24 despite extensive evolutionary divergence, and glycocalyx profiling revealed broad remodeling of the tumor cell surface upon CD24 loss, suggesting evolutionary conservation of sialic acid-dependent receptor recognition. Transcriptomic analyses identified the Siglec-like gene si:dkey-24p1.7 as a candidate zebrafish macrophage-expressed receptor mediating this response. Finally, analysis of TCGA CRC cohorts revealed that CD24 expression is a stage-dependent prognostic marker, underscoring the clinical relevance of this axis. Together, these findings establish CD24 as a critical orchestrator of innate immune evasion in CRC, while further validating zebrafish xenografts as a powerful platform for dissecting innate immuno-oncobiology in vivo.

cancer biology↗

bioRxiv2025

Biliverdin Reductase Catalytic Activity Is Essential for Malaria Resistance

Jaundice, a condition characterized by elevated levels of circulating bilirubin, is an adaptive response to malaria sustained through bilirubin production by biliverdin reductase A (BVRA). Beyond its enzymatic activity, BVRA acts as a protein kinase and as a transcription factor. To disentangle the contribution of BVRA catalytic activity over its non-canonical functions we generated BlvraG17A and BlvraE97A mice harboring G17A and E97A missense mutations in the BVRA NAD(P)H-binding domain and reductase motif, respectively. Both BlvraG17A and BlvraE97Amice presented a reduction in enzymatic activity and succumbed to malaria, otherwise non-lethal to wild-type (BlvraWT) mice. Quantification of circulating unconjugated bilirubin revealed a dose response effect whereby the mutant strains failed to reach a threshold of circulating bilirubin required to support its protective effect. These findings establish the antimalarial effect of the enzymatic activity of BVRA and define a concentration threshold of bilirubin required for malaria protection, informing therapeutic development and biomarker-guided malaria treatment strategies. Highlights- Establishment of catalytic deficient BVRA mouse mutants; - Anti-malarial effect of BVRA relies on its catalytic activity; - A minimal bilirubin threshold for parasite control; - A minimal bilirubin threshold for malaria resolution;

pathology↗

bioRxiv2024

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

developmental biology↗

bioRxiv2021

A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

immunology↗