Biology subjects

Esteve-Codina, A.

Publications and source records attributed to Esteve-Codina, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling

Tumor heterogeneity is a major determinant of tumor progression and therapeutic resistance, yet the contribution of metabolism to intratumoral heterogeneity still remains poorly explored. Here, we find that pyruvate dehydrogenase kinase-1 (Pdk1) expression defines metabolically distinct cancer cell populations in colorectal tumors. Image-based spatial single-cell phenotyping shows that Pdk1-high cells are associated with tumor progression in orthotopic models of colorectal cancer (CRC). Genetic ablation experiments demonstrate the role of Pdk1-high cells in tumor growth, 5-fluorouracil chemoresistance and tumor relapse. Mechanistically, we identify a link between Pdk1-driven metabolic states and specific cell phenotypes, where Pdk1-high cancer cells exhibit an EMT, stem cell-like phenotype characterized by increased interferon (IFN) signaling. Mitochondrial remodeling in Pdk1-high cells leads to the release of mitochondrial DNA to the cytosol and activation of IFN pathways, promoting Pdk1-driven phenotypes. Inhibition of IFN signaling impairs the tumorigenic and aggressive features of Pdk1-high cancer cells, thus establishing a functional connection between metabolic heterogeneity, cell-intrinsic IFN signaling and aggressive CRC.

cancer biology↗

bioRxiv2026

Synergistic effects of hypergravity and immune challenge on the zebrafish larval transcriptome

The transcriptomic interaction between altered gravity and innate immunity remains largely unexplored. In this study, we established a novel dual-stress model combining 3g hypergravity with lipopolysaccharide (LPS) immune challenge in 5 days post-fertilization (dpf) zebrafish (Danio rerio) larvae. RNA sequencing revealed that exposure to hypergravity alone induced no differentially expressed genes (DEGs), indicating a remarkable transcriptional resilience. In contrast, the addition of an immune challenge under hypergravity conditions triggered a substantial transcriptomic response involving 2,706 DEGs. Functional enrichment analyses identified significant alterations in pathways related to immune function, development, and circadian regulation. Targeted qPCR analyses further validated the expression patterns of selected genes. These findings suggest that while zebrafish larvae can effectively tolerate hypergravity alone, the combination of gravitational and immune stressors elicits profound molecular responses. This study provides new insights into the interplay between altered gravity and innate immunity using an animal model, contributing to future strategies aimed at safeguarding astronaut health and supporting space-based aquaculture systems.

genomics↗

bioRxiv2026

PI3K signaling promotes inflammatory tumor-macrophage crosstalk associated with mesenchymal glioblastoma

BackgroundGlioblastoma (GBM) is a highly heterogeneous and vascularized malignancy in which the mesenchymal (MES) subtype is associated with poor prognosis, extensive macrophage infiltration and resistance to therapy. However, the signaling mechanisms integrating vascular remodeling with inflammatory tumor-macrophage crosstalk remain incompletely understood. MethodsWe integrated magnetic resonance imaging-derived vascular phenotyping with transcriptomic analyses of human glioblastoma cohorts to identify molecular pathways associated with highly vascular tumors. Functional studies using glioblastoma cell lines, THP-1-derived macrophages and co-culture systems were performed to investigate the role of PI3K signaling in tumor-macrophage communication. Finally, an independent single-cell transcriptomic cohort of primary human glioblastoma was interrogated to determine whether the identified inflammatory programs were conserved in malignant cells from patient tumors. ResultsIntegrated imaging-transcriptomic analyses identified highly vascular glioblastomas as tumors enriched for the MES subtype, increased macrophage infiltration and activation of PI3K-associated signaling. Pharmacological inhibition of PI3K reduced the expression of macrophage-recruiting cytokines and impaired the ability of glioblastoma cells to educate macrophages toward an immunosuppressive phenotype. Reciprocally, tumor-educated macrophages enhanced inflammatory signaling, immune checkpoint expression and migratory capacity in glioblastoma cells, whereas IL-6 blockade attenuated these effects, identifying IL-6 as a key mediator of this bidirectional communication. To determine whether these inflammatory programs were conserved in human disease, we analyzed an independent single-cell transcriptomic dataset of primary glioblastomas. MES-like malignant cells exhibited the strongest inflammatory transcriptional programs among the four malignant transcriptional states, including higher NF-{kappa}B activation program scores and tumor-macrophage communication signature scores. At the tumor level, MES-like enrichment was positively associated with higher inflammatory program activity, supporting the clinical relevance of the proposed signaling axis. ConclusionsTogether, our findings identify PI3K signaling as a central regulator integrating vascular remodeling with inflammatory tumor-macrophage communication in mesenchymal glioblastoma. These results provide a mechanistic framework linking PI3K signaling, macrophage education and the MES phenotype, and provide a rationale for therapeutic strategies aimed at disrupting inflammatory signaling within the glioblastoma microenvironment.

cancer biology↗

bioRxiv2026

In vivo CRISPR-based screen identifies ZC3H12C as a mediator of CAR-T cell dysfunction in solid tumors

CAR-T cell therapy has shown limited efficacy in solid tumors, largely due to T cell dysfunction driven by chronic antigen exposure. To uncover mediators of this dysfunction, we developed an in vivo screening platform using an ovarian xenograft tumor model in which CD28-based CAR-T cells undergo exhaustion leading to tumor escape. Transcriptomic profiling of tumor-infiltrating CAR-T cells at different stages revealed dynamic upregulation of exhaustion-associated genes. We used this data to design a focused CRISPR/Cas9 library and performed an in vivo screen. We identified 14 significantly enriched candidate genes, among which ZC3H12C emerged as the top hit. Single-cell RNA and ATAC-seq confirmed ZC3H12C expression in CAR-T cells undergoing early exhaustion in vivo. ZC3H12C disruption enhanced CAR-T cell persistence and antitumor efficacy while reducing exhaustion, across both CD28- and 4-1BB-based CARs targeting distinct antigens. These results highlight ZC3H12C as a promising target to improve CAR-T therapy in solid tumors.

immunology↗

bioRxiv2026

HERVs as building blocks of RNA regulatory architecture in the human genome

Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and have contributed extensively to gene regulatory evolution. However, their roles in RNA-centered regulatory processes remain poorly characterized. Here, we present a genome-wide annotation of RNA regulatory features embedded within HERV internal regions and long terminal repeats (LTRs), revealing that HERV sequences act as pervasive components of the human transcriptome. Systematic analysis of RNA-binding protein (RBP) motifs uncovers structured, family-specific regulatory architectures, with distinct RBP signatures distinguishing major HERV subfamilies. Notably, HERVH elements are enriched for RBPs associated with developmentally regulated RNA processing, whereas HERVK (HML-2) elements preferentially harbor motifs linked to canonical splicing and mRNA maturation. Integration with gene annotations reveals widespread incorporation of HERV sequences into transcript structures, including more than 4,000 long non-coding RNAs. Conserved retroviral protein domains within predicted open reading frames are strongly enriched in terminal exons and 3' untranslated regions, consistent with potential micropeptide-encoding capacity. In addition, we identify a subclass of lncRNAs largely composed of HERV sequence, indicating that endogenous retroviral loci have been extensively captured within annotated transcripts. Finally, we detect more than 6,500 antisense LTR insertions in transcript termini, defining widespread SPARCS-like (stimulated 3 prime antisense retroviral coding sequences) configurations with potential for double-stranded RNA formation and preferential association with immune-related genes. Together, these results establish HERV sequences as a pervasive layer of RNA regulatory potential embedded within human transcripts, highlighting previously underappreciated roles in post-transcriptional gene regulation.

genomics↗

bioRxiv2026

Regulatory Features and Functional Specialization of Human Endogenous Retroviral LTRs: A Genome-Wide Annotation and Analysis via HERVarium

Human endogenous retroviruses (HERVs), remnants of ancient retroviral infections, account for over 8% of the human genome and remain an underexplored source of cis-regulatory elements and protein-coding remnants. Here we present HERVarium, an integrated and interactive database that provides access to systematic annotations of the protein-domain architecture of internal HERV regions and the regulatory landscape of their LTRs across the human genome. Building on our previous catalog of conserved retroviral domains, we classified over 400,000 LTRs by structure (solo, 5', or 3' LTR), proximity to transcription start sites (TSS), potential transcription-factor binding-motif (TFBM) burden, and computationally reconstructed their canonical U3-R-U5 substructure, revealing that two-thirds retain recognizable segmentation, particularly those adjacent to conserved internal domains. LTRs flanking internal regions with conserved Gag, Pol, or Env domains tend to be longer and richer in motifs, suggesting coordinated maintenance of coding and regulatory potential. Conversely, solo LTRs positioned at gene TSSs exhibit promoter-like architectures enriched in motifs for developmental and proliferative regulators, while selectively lacking motifs associated with neuronal differentiation. Some 5' LTRs at lncRNA TSSs also flank conserved retroviral domains, indicating that certain lncRNAs may derive from transcriptionally active, structurally intact HERV loci. HERVarium provides a comprehensive, interactive resource to explore and download these annotations at single-locus resolution.

genomics↗

bioRxiv2025

Single-Cell Dissection of Immunometabolic Rewiring in the Porcine Ileum during Salmonella Typhimurium Infection

Salmonella Typhimurium is a major zoonotic pathogen, with pigs acting as important subclinical carriers. To explore the specific intestinal immune response at the cellular level, we used Single-cell RNA sequencing (scRNA-seq), enabling detailed analysis of immune cell types and gene expression profiles during infection. In addition to enterocytes, our results revealed the presence of diverse immune populations, including monocytes/macrophages, dendritic cells, innate lymphoid cells (ILCs), thirteen T cell subtypes and five B cell populations were identified, revealing pronounced infection-driven alterations in cellular composition and transcriptional states. Among T cells, naive and follicular CD4+/CD8+ {beta} T cells and NK T cells were expanded, whereas effector CD8+ T cells and CD2- and SELLhi {gamma}{delta} T cells were decreased. B-cell populations shifted toward activated and cycling states, with decreased antibody-secreting, resting, and transitioning cells. Dendritic cells and monocyte/macrophage populations were expanded, and group 3 ILCs and enterocytes were markedly reduced. Pathway analyses revealed robust cell type-specific immunometabolic remodeling, including enhanced protein-folding and stress-adaptive pathways in T and B cells, heightened inflammatory, interferon, and cytokine signaling in myeloid populations, and coordinated metabolic and immune adjustments in epithelial cells, highlighting the complexity of host responses to Salmonella infection. This study provides the first scRNA-seq landscape of the porcine ileum during S. Typhimurium infection, offering insight into host immune cell dynamics and immunometabolic responses.

genomics↗

bioRxiv2025

TRIP13 fosters both transcriptional silencing and DSB repair during meiosis

During meiosis, the coordinated suppression of global gene transcription and induction of double-strand breaks (DSBs) genome wide is crucial for successful gamete formation. The AAA+ ATPase TRIP13 is a master meiotic regulator involved in numerous cellular processes, including DSB repair, organization of the meiotic chromosome axis, and meiotic silencing of unsynapsed axes. Here, we examine the involvement of TRIP13 in transcription suppression and DSB repair during meiotic prophase I in mice. Because TRIP13 is required for silencing of sex chromosomes at pachynema, we hypothesized that it may also be involved in the global transcription suppression that begins at the onset of meiotic prophase. Indeed, as predicted, we observed increased incorporation of 5-ethynyl uridine in early stages of meiotic prophase I and a higher presence of the active form of RNA polymerase II in Trip13 mutant spermatocytes. RNA sequencing data revealed that more than two-thirds of upregulated transcripts came from the sex chromosomes. Given this more general role in transcription silencing, we also tested whether TRIP13 promotes the transcription block that causes meiotic arrest in synapsis-deficient oocytes. However, Trip13 ablation did not rescue Spo11-/- oocytes, which experience asynapsis without DSB repair defects. Instead, Trip13 mutation did increase the number of oocytes in Dmc1-/- Chk2-/- mice, in which DSBs persist unrepaired. This rescue seems attributable to a previously unknown function of TRIP13 in preventing DSB repair by non-canonical pathways, as we observed fewer homologous recombination markers along with an increased presence of non-homologous end joining markers in the triple mutant cells. These findings underscore TRIP13s multifaceted role in transcription and DSB repair regulation during meiosis, highlighting its importance and potential for further meiotic regulation and fertility research.

cell biology↗

bioRxiv2025

A Comprehensive Annotation of Conserved Protein Domains in Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) occupy nearly 8% of the human genome, yet their protein-coding potential remains largely unexplored. HERVs originate from ancestral exogenous retroviruses that infected germline cells and became integrated into the human genome. Like their exogenous counterparts, they typically follow the canonical proviral structure: LTR-gag-pol-env-LTR, where gag, pol, and env encode structural, enzymatic, and envelope proteins, respectively. Here, we present a comprehensive resource annotating conserved retroviral domains across 120,000+ ORFs derived from internal HERV regions. Using a reproducible pipeline based on HMMER and InterProScan, we identified over 17,000 domain hits--primarily from pol genes such as reverse transcriptase, RNase H, and protease--and quantified their structural conservation. Hundreds of domains exceed 95% alignment coverage, revealing a surprising abundance of full-length, retrovirus-like domains in both young and ancient HERV families. While the HERVK subfamily retains the most complete polyprotein architecture--including 13 loci with nearly intact Gag, Pol, and Env domains--many full-length Pol domains are also found in other families such as HERVH, HERVW, and HERVE. Our high-resolution annotations recover conserved catalytic motifs in Pol domains and transmembrane features in Env, enabling fine-grained functional interpretation. All annotations--including BED, FASTA, domain sequences, InterProScan outputs, and transmembrane predictions--are provided as an open resource for functional genomics and HERV expression studies at Zenodo (DOI: https://doi.org/10.5281/zenodo.17129661). This dataset will support downstream analyses of HERV protein expression, immune modulation, and co-option, in diseases and normal physiological conditions.

genomics↗

bioRxiv2025

Dorsal Striatum Parvalbumin interneurons translatome unveiled

Parvalbumin (PV) interneurons in the dorsal striatum (DS) are fast-spiking GABAergic cells critical for feedforward inhibition and synaptic integration within basal ganglia circuits. Despite their well-characterized electrophysiological roles, their molecular identity remains incompletely defined. Using the Ribotag approach in Pvalb-Cre mice, we profiled the translatome of DS PV interneurons and identified over 2,700 transcripts significantly enriched (fold-change > 1.5) in this population. Our data validate established PV markers and reveal a distinct molecular signature of DS PV neurons compared to PV interneurons from the nucleus accumbens. Gene ontology analyses highlight prominent expression of genes related to extracellular matrix components, cell adhesion molecules, synaptic organization, ion channels, and neurotransmitter receptors, particularly those mediating glutamatergic and GABAergic signaling. Notably, perineuronal net markers were robustly expressed in DS PV interneurons and confirmed by immunofluorescence. Transcriptomic analysis of DS PV neurons following repeated d-amphetamine exposure identified Gm20683 as the only differentially expressed transcript between treated groups. Furthermore, RNAseq analysis of mice subjected to an operant behavior paradigm with two types of food reward (high-palatable diet or standard chow) identified over 1,000 and 100 genes enriched in DS PV neurons from standard and high-palatable masters, respectively. These findings provide a comprehensive molecular profile of DS PV interneurons, distinguishing them from other striatal PV populations, and reveal specific gene expression changes associated with psychostimulant exposure and reward-driven behaviors. Our findings deepen insight into the molecular mechanisms of PV interneuron activity in striatal circuits and their potential roles in neuropsychiatric, motor and reward-related disorders.

neuroscience↗

bioRxiv2025

Early downregulation of HC-specific genes in the vestibular sensory epithelium during chronic ototoxicity

Exposure of mammals to ototoxic compounds causes hair cell (HC) loss in the vestibular sensory epithelia of the inner ear. In chronic exposure models, this loss often occurs by extrusion of the HC from the sensory epithelium towards the luminal cavity. HC extrusion is preceded by several steps that begin with detachment and synaptic uncoupling of the cells from the afferent terminals of their postsynaptic vestibular ganglion neurons. The purpose of this study was to identify gene expression mechanisms that drive these responses to chronic ototoxic stress. We conducted four RNA-seq experiments that generated five comparisons of control versus treated animals. These involved two species (rat and mouse), two compounds (streptomycin and 3,3-iminodipropionitrile, IDPN), and three time points in our rat/IDPN model. We compared differentially expressed genes and their associated Gene Ontology terms, and several genes of interest were validated by in-situ hybridisation and immunofluorescence analyses. Common and model-unique expression responses were identified. The earliest and most robust common response was downregulation of HC-specific genes, including stereocilium (Atp2b2, Xirp2), synaptic (Nsg2), and ion channel genes (Kcnab1, Kcna10), together with new potential biomarkers of HC stress (Vsig10l2). A second common response across species and compounds was the upregulation of the stress mediator Atf3. Model- or time-restricted responses included downregulation of cell-cell adhesion and mitochondrial ATP synthesis genes, and upregulation of the interferon response, unfolded protein response, and tRNA aminoacylation genes. The present results provide key information on the responses of the vestibular sensory epithelium to chronic ototoxic stress, potentially relevant to other types of chronic stress.

neuroscience↗

bioRxiv2024

ASMS: finding allele specific methylation in human genomes without phasing

MotivationAllele-specific methylation (ASM) refers to differential DNA methylation patterns between two alleles at a given locus. This phenomenon is often driven by genetic variants, such as single nucleotide variants (SNVs), which influence methylation in cis by affecting transcription factor or methylation regulator binding, leading to allele-specific differences. Understanding ASM is critical for elucidating gene regulation, as it impacts gene expression and contributes to normal biological variation as well as disease processes, including cancer [1] and autoimmune disorders [2],[3]. Another key driver of ASM is genomic imprinting, an epigenetic mechanism in which gene expression is regulated in a parent-of-origin-specific manner. Imprinted regions, marked during gametogenesis and maintained through cell divisions, are essential for growth, development, and metabolism. Dysregulation of imprinting is associated with developmental and metabolic disorders, such as Prader-Willi and Angelman syndromes, and certain cancers. Detecting ASM across the genome remains challenging due to its tissue- and cell-specific nature and the technical difficulty of phasing reads to assign methylation patterns to specific alleles. Current ASM detection pipelines (e.g., [4])) often require phasing via genetic variants, a computationally intensive process that is limited in regions with low heterozygosity. ResultsTo address these limitations, we developed asms (Allele-Specific Methylation Scanner), a tool designed to detect ASM directly from methylation data without the need for prior phasing. asms offers a faster and complementary approach to uncovering the regulatory effects of ASM, particularly in genomic regions where genetic variants or imprinting play a critical role. For demonstration purposes we leverage the fact that reads generated by Oxford Nanopore (ONT) technology measure sequence and methylation status at once, but the same software can be used with other sequencing technologies. asms can check thousands of loci in a short time. The initial list of loci to examine can be given by the user, or generated by asms through a genomic scan. The asms cluster subcommand separates the reads based on methylation. If phasing results are available, asms can use them to verify whether distinct alleles correspond to distinct base modifications patterns. We benchmark our software using publicly available Ashkenazi trio data [5]. Implementation and availabilityasms is implemented in rust and python. The software is available at https://github.com/ecmra/asms.

bioinformatics↗

bioRxiv2024

The Draparnaldia genome: alternative mechanisms for multicellularity and terrestrialization in green plants

Green plants contain two algal lineages: Streptophyte algae that diverged into land plants and Chlorophyte algae that are mostly aquatic. Draparnaldia is a Chlorophyte alga morphologically resembling mosses and living in both, the aquatic and terrestrial habitats. Because of its complex morphology and terrestrial adaptations, Draparnaldia can provide new insights into the evolution of multicellularity and terrestrialization in green plants. To develop Draparnaldia into a model, we de novo sequenced its genome and transcriptomes, and profiled its phytohormone repertoire. We found that 1) Expanded gene families in Draparnaldia with respect to unicellular Chlamydomonas are linked to multicellularity and abiotic stresses. 2) Draparnaldias terrestrial adaptations are reflected at both the morphological and molecular levels. 3) Draparnaldia synthesizes most of the phytohormones used by land plants to thrive in terrestrial habitats. All of this makes Draparnaldia a powerful model to uncover and study alternative evolutionary trajectories towards multicellularity and terrestrialization in plants.

evolutionary biology↗

bioRxiv2024

Revealing the Prevalence of Suboptimal Cells and Organs in Reference Cell Atlases: An Imperative for Enhanced Quality Control

The advent of droplet-based single-cell RNA-sequencing (scRNA-seq) has dramatically increased data throughput, enabling the release of a diverse array of tissue cell atlases to the public. However, we will show that prominent initiatives such as the Human Cell Atlas, Tabula Muris, and Tabula Sapiens contain a significant amount of contamination products (frequently affecting the whole organ) in their data portals due to suboptimal quality filtering. Our work addresses a critical gap by advocating for more stringent quality filtering, highlighting the imperative for a shift from existing standards, which currently lean towards greater permissiveness. We will show the importance of incorporating cell intronic fraction in quality control -or MALAT1 expression otherwise- showcasing its informative nature and potential to elevate cell atlas data reliability. In summary, here, we unveil the hidden intronic landscape of every tissue and highlight the importance of more rigorous single-cell RNA-sequencing quality assessment in cell atlases to enhance their applicability in diverse downstream analyses.

bioinformatics↗

bioRxiv2023

The hepatocyte Epidermal Growth Factor Receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Background & AimsLiver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of profibrotic factors are not well characterized. The Epidermal Growth Factor Receptor (EGFR) signaling in hepatocytes is essential for the regenerative process of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Approach & ResultsOur group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes ({Delta}EGFR mice). Here, we have analyzed the response of WT and {Delta}EGFR mice to chronic treatment with CCl4. Resultsindicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated {Delta}EGFR mice when compared to WT mice, coinciding with a faster resolution of the fibrotic process and an ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable change in the population of M2 macrophages, more related to fibrosis resolution, as well as an increase in the population of lymphocytes related to eradication of the damage. Transcriptomic analysis of hepatocytes and secretome studies from extracellular media in in vitro studies allowed to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-inflammatory and pro-fibrotic mediators. ConclusionsOur results support a pro-inflammatory and pro-fibrogenic role for the hepatocyte EGFR pathway during chronic liver damage.

pathology↗

bioRxiv2023

A human in vitro neuronal model for studying homeostatic plasticity at the network level

Mechanisms that underlie homeostatic plasticity have been extensively investigated at single-cell levels in animal models, but are less well understood at the network level. Here, we used microelectrode arrays to characterize neuronal networks following induction of homeostatic plasticity in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with rat astrocytes. Chronic suppression of neuronal activity through tetrodotoxin (TTX) elicited a time-dependent network re-arrangement. Increased expression of AMPA receptors and the elongation of axon initial segments were associated with increased network excitability following TTX treatment. Transcriptomic profiling of TTX-treated neurons revealed up-regulated genes related to extracellular matrix organization, while down-regulated genes related to cell communication; also astrocytic gene expression was found altered. Overall, our study shows that hiPSC-derived neuronal networks provide a reliable in vitro platform to measure and characterize homeostatic plasticity at network and single-cell level; this platform can be extended to investigate altered homeostatic plasticity in brain disorders.

neuroscience↗

bioRxiv2022

Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells

Latency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1- infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal.

immunology↗

bioRxiv2022

A TetR-like transcriptional regulator in Stenotrophomonas maltophilia involved in fatty acid metabolism is controlled by quorum sensing signals

Stenotrophomonas maltophilia is an environmental bacterium and it is also an emerging opportunistic multidrug-resistant pathogen. It uses the endogenous DSF quorum sensing (QS) system to coordinate population behaviors and to regulate virulence processes but can also respond to exogenous AHL signals produced by neighboring bacteria. Whole-transcriptome sequencing analyses were performed for S. maltophilia K279a in the exponential and stationary phases as well as in exponential cultures after treatment with exogenous DSF or AHLs. The results revealed that at the beginning of the stationary phase 1673 genes are differentially expressed. COG analysis showed that most of these genes were enriched for energetic metabolism processes and regulation of gene expression. After adding DSF or AHLs, 28 or 82 genes were found deregulated, respectively, 22 of which upregulated by both autoinducers. Interestingly, among these later genes, 14 were also upregulated in the stationary phase. Gene functions regulated by all conditions include lipid and amino acid metabolism, stress response and signal transduction, nitrogen and iron metabolism, and adaptation to microoxic conditions. Among the common top upregulated QS core genes, a putative TetR-like regulator (Smlt2053) was selected for functional characterization. This regulator has been shown to control a narrow regulon, including its own operon. It was found to sense long-chain fatty acids, including the QS signal DSF, and regulate a {beta}-oxidation catabolic pathway. Overall, our findings provide clues on the role that the QS could have in S. maltophilia in the transition from the exponential to the stationary phase and bacterial fitness under high-density growth. IMPORTANCEThe quorum sensing system in Stenotrophomonas maltophilia, in addition to coordinating the bacterial population, controls virulence-associated phenotypes, such as biofilm formation, motility, protease production, and antibiotic resistance mechanisms. Biofilm formation is frequently associated with the persistence and chronic nature of nosocomial infections. In addition, biofilms exhibit high resistance to antibiotics, making treatment of these infections extremely difficult. The importance of studying the metabolic and regulatory systems controlled by quorum sensing autoinducers will make it possible to discover new targets to control pathogenicity mechanisms in S. maltophilia.

microbiology↗