Biology subjects

Rivero, A.

Publications and source records attributed to Rivero, A..

14 recordsLinked to original sources

bioRxiv2026

Cancer cachexia overrides sex-specific traits in Drosophila

Cancer cachexia, a metabolic syndrome characterized by pathologic weight loss, dramatically limits therapeutic options and reduces survival. While the mechanisms by which tumors induce wasting of distant organs (particularly muscle and adipose tissues) remain incompletely understood, the influence of biological sex on cachexia progression is even less clear. Here we investigated phenotypic and molecular manifestations of cachexia in both sexes using a model of inducible intestinal tumors in Drosophila. We show that tumor progression leads to the development of severe cachexia both in males and in females manifested by organ atrophies and an inflammatory state. Nevertheless, both phenotypical and molecular cachexic alterations exhibit striking differences between sexes. Transcriptomic analysis show that many genes differentially expressed at high levels in males under normal conditions become downregulated during cachexia, while their expression is upregulated in cachexic females, and reciprocally. Together, sex-specific deregulation in gene expression and metabolic profiles ultimately converge towards a molecular cachexic state that erase or diminish many sex-specific differences otherwise characteristic of healthy males and females. These findings highlight the interplay between oncogenic stress and biological sex in shaping cachexia phenotypes, shedding light on how sex influences the development of cancer cachexia.

developmental biology↗

bioRxiv2026

The genome of the avian malaria parasite Haemoproteus majoris (lineage WW2) and its relationship to other Plasmodium species

Avian malaria parasites form a highly prevalent and genetically diverse group within the haemosporidians, yet they have long been overlooked relative to their human- and rodent-infecting counterparts. Among these, parasites of the genus Haemoproteus (Haemosporida, Haemoproteidae) are widespread and prevalent blood parasites of birds, transmitted by louse flies (Hippoboscidae) and biting midges (Ceratopogonidae). Recent phylogenomic analyses place Haemoproteus parasites at the root of the haemosporidian tree, making genomic data from these taxa essential for understanding the evolutionary origins of malaria parasites. To date, only two avian Plasmodium and one avian Haemoproteus genomes have been sequenced. We present the first assembled genome of Haemoproteus majoris (lineage WW2), a common blood parasite of passerine birds. As avian erythrocytes are nucleated, parasite DNA was enriched by FACS-based sorting to discriminate and isolate the parasite from host cell nuclei prior to whole-genome amplification. The genome was assembled using Nanopore long-read sequencing and polished with Illumina short-reads, yielding 145 contigs with a total assembly size of 23.9Mb and a G+C content of 27.85%. Genome annotation identified 5501 protein-coding genes, 69 non-coding RNA genes, and 57 long terminal repeat retrotransposons (LRT-RTs), including one full-length element. This genomic resource represents a critical step towards elucidating the evolutionary history and genomic architecture of avian malaria parasites. SIGNIFICANCE STATEMENTWe present the first assembled genome of Haemoproteus majoris (lineage WW2), a prevalent and generalist avian malaria parasite. Taxonomic resolution of this genus is difficult as there are few distinct morphological differences among closely-related species. This genome provides a valuable resource for studying the evolution within the Haemoproteus genus and to elucidate the evolutionary history of malaria parasites.

genomics↗

bioRxiv2025

Single cell transcriptomics and development of gametocyte-specific molecular markers for avian malaria parasites

Avian malaria, caused by Plasmodium parasites, poses a significant threat to bird populations worldwide, particularly in vulnerable island ecosystems. Yet, progress in understanding avian malaria transmission dynamics has been hampered by the lack of molecular tools to quantify and sex the transmissible stages of the parasite: the male and female gametocytes. This challenge is compounded by the nucleated erythrocytes of avian hosts and the absence of an in vitro culture system, which have historically hindered the advancement of molecular approaches. Here, we develop and validate the first molecular markers to discriminate between asexual, male, and female gametocytes in the widespread avian malaria parasite Plasmodium relictum. Using single-cell RNA sequencing and orthology-guided stage mapping, we identified conserved, stage-specific transcripts and leveraged this information to develop molecular markers capable of quantifying and distinguishing male and female gametocytes in two parasite cyt-b lineages, pSGS1 and pDELURB. These markers outperformed microscopy in sensitivity, detected gametocytes earlier and for longer, and revealed consistently higher male-to-female gametocyte ratios than estimated by blood smears. The high degree of conservation of these markers across Plasmodium species suggests broad applicability of these markers to other avian lineages.

molecular biology↗

bioRxiv2025

The Mediator complex subunit Med19 extends healthy lifespan in Drosophila by preventing cellular and organismal frailty

Aging involves a progressive decline in physiological functions, often marked by the onset of a "frailty point" just before survival rates decrease rapidly. Here, we investigate how the Mediator subunit Med19 modulates this transition in Drosophila. We find that upregulating Med19 extends the median lifespan by nearly 90% and postpones the onset of accelerated mortality, suggesting that Med19 helps preserve the resilience phase of aging. In contrast, Med19 downregulation sharply reduces both median and maximum lifespan, advancing the frailty threshold. We show that Med19 knockdown increases fly vulnerability to environmental insults such as oxidative and genotoxic challenges whereas Med19 upregulation helps them resist these stresses, underscoring Med19s protective role in maintaining genomic integrity. We link these phenotypes to altered stress-response pathways at the cellular level: Med19-depleted cells show a compensatory upregulation of genes involved in iron-sulfur cluster biogenesis, glutathione metabolism, and DNA damage repair. At the cellular level, Med19 depletion triggers a "loser" phenotype in cell competition assays, activating the JNK pathway and undergoing apoptosis, highlighting a form of "cellular frailty" that parallels organismal frailty. Finally, we found that the Med19 protein level naturally decreases with age and showed that restoring Med19 expression in aged flies increases fitness and delays the onset of frailty even in older, "frail" individuals, underscoring its significance as an aging regulator. Altogether, our findings establish Med19 as a crucial mediator of lifespan and stress resilience, suggesting it acts as a rheostat that modulates the transition from healthy aging to frailty in Drosophila. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/659864v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1a5e398org.highwire.dtl.DTLVardef@14658org.highwire.dtl.DTLVardef@1b14089org.highwire.dtl.DTLVardef@41060_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- At the organismal level, Med19 upregulation extends Drosophila lifespan by 90%, delays the onset of frailty and enhances oxidative and DNA damage stress resistance, while its depletion has the opposite effect. - Med19 depletion alters the expression of stress response genes and induces a loser-cell phenotype in cell competition assays revealing its crucial function in controlling cellular fitness. - Med19 protein levels naturally decline with age, and its restoration in aged flies improves both healthspan and lifespan.

cell biology↗

bioRxiv2024

Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms

Translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain unexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show that in vitro induced MCL-associated translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Additionally, overexpressed genes in MCL patients are enriched in the exact same genomic regions, further underlining its potential relevance for lymphomagenesis. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression residing in pre-existing long-range interacting loops spanning 50 megabases. The translocation places the strong immunoglobulin enhancer into this loop, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, we show that translocations can induce ample, simultaneous gene expression changes affecting entire chromosome arms, representing an important new mechanism for tumorigenesis.

cancer biology↗

bioRxiv2024

Beyond immunity: a transcriptomic landscape of Plasmodium's modulation of mosquito metabolic pathways

The focus of mosquito-Plasmodium interactions has predominantly been centered on mosquito immunity, revealing key mechanisms by which mosquitoes attempt to combat Plasmodium infection. However, recent evidence suggests that beyond immunity, a multitude of mosquito physiological and metabolic pathways play crucial roles in determining whether the parasite completes its development within the mosquito. We review which of these metabolic pathways are potentially modulated by Plasmodium, revealing a fragmented and occasionally contradictory state of knowledge. We then present a comprehensive transcriptomic analysis of Plasmodium-infected and uninfected mosquitoes, examining gene expression of crucial genes across different stages of the parasites development. These genes range from key enzymes and proteins involved in gut structure and function, to genes involved in egg production and resorption, salivary gland invasion and mosquito behaviour. For this purpose, we use a non-model system consisting of the avian malaria parasite Plasmodium relictum, an invasive parasite threatening bird biodiversity across the world, and its natural vector, the mosquito Culex pipiens. Our results reveal how at each stage of its development within the mosquito, Plasmodium modulates a myriad of mosquito metabolic pathways, in ways that potentially favour its survival and the completion of its life cycle. We discuss whether this constitutes sufficient evidence of parasite-driven manipulation or whether the changes are simply the mosquitos response to the infection, which the parasite may serendipitously exploit to enhance its fitness. Our study extends the comparative transcriptomic analyses of malaria-infected mosquitoes beyond human and rodent parasites, and provides insights into the degree of conservation of metabolic pathways and into the selective pressures exerted by Plasmodium parasites on their vectors.

genomics↗

bioRxiv2023

Crosstalk between chromatin and the transcription factor Shavenbaby defines transcriptional output along the Drosophila intestinal stem cell lineage.

The transcription factor Shavenbaby (Svb), the only member of the OvoL family in Drosophila, controls intestinal stem cell differentiation. Post-translational modification of Svb produces two protein isoforms, Svb-ACT and Svb-REP, which promote intestinal stem cell renewal or differentiation, respectively. Using engineered cell lines, we express either isoform to define their mode of action, and develop an unbiased method to identify Svb target genes in intestinal cells. Within a given cell type, Svb-ACT and Svb-REP antagonistically regulate the expression of a set of target genes, binding specific enhancers whose accessibility is constrained by. During intestinal differentiation, the set of target genes progressively changes, together with chromatin accessibility. Moreover, Svb-REP binding stabilizes three-dimensional enhancer-promoter loops, while influencing the local chromatin landscape to repress target genes. We propose that SvbACT-to-REP switch promotes enterocyte differentiation of intestinal stem cells through direct gene regulation and chromatin remodeling.

genomics↗

bioRxiv2022

Immune gene expression in the mosquito vector Culex quinquefasciatus during an avian malaria infection

Plasmodium relictum is the most widespread avian malaria parasite in the world. It is listed as one of the 100 most dangerous invasive species, having been responsible for the extinction of several endemic bird species, and the near-demise of several others. Here we present the first transcriptomic study examining the effect of P. relictum on the immune system of its vector (the mosquito Culex quinquefasciatus) at different times post-infection. We show that over 50% of immune genes identified as being part of the Toll pathway and 30-40% of the immune genes identified within the Imd pathway are overexpressed during the critical period spanning the parasites oocyst and sporozoite formation (8-12 days), revealing the crucial role played by both these pathways in this natural mosquito-Plasmodium combination. Comparison of infected mosquitoes with their uninfected counterparts also revealed some unexpected RNA expression patterns earlier and later in the infection: Significant differences in expression of several immune effectors were observed as early as 30 minutes after the ingestion of the infected blood meal. In addition, in the later stages of the infection (towards the end of the mosquito lifespan), we observed an unexpected increase in immune investment in uninfected, but not in infected, mosquitoes. In conclusion, our work extends the comparative transcriptomic analyses of malaria-infected mosquitoes beyond human and rodent parasites and provides insights into the degree of conservation of immune pathways and into the selective pressures exerted by Plasmodium parasites on their vectors.

evolutionary biology↗

bioRxiv2022

Fitness costs and benefits in response to artificial artesunate selection in Plasmodium

AO_SCPLOWBSTRACTC_SCPLOWDrug resistance is a major issue in the control of malaria. Mutations linked to drug resistance often target key metabolic pathways and are therefore expected to be associated with biological costs. The spread of drug resistance depends on the balance between the benefits that these mutations provide in the drug-treated host and the costs they incur in the untreated host. The latter may therefore be expressed both in the vertebrate host and in the vector. Research on the costs of drug resistance focusses on interactions with vertebrate host, yet whether they are also expressed in the vector has been overlooked. In this study, we aim to identify the costs and benefits of resistance against artesunate (AS), one of the main artemisinin derivatives used in malaria-endemic countries. For this purpose, we compared different AS-selected lines of the avian malaria parasite Plasmodium relictum to their ancestral (unselected) counterpart. We tested their within host dynamics and virulence both in the vertebrate host and in its natural vector, the mosquito Culex quinquefasciatus. The within-host dynamics of the AS-selected lines in the treated birds was consistent with the phenotype of resistance described in human P. falciparum malaria: a clearance delay during the treatment followed by a recrudescence once the treatment was interrupted. In the absence of treatment, however, we found no significant costs of resistance in the bird. The results of the two experiments to establish the infectivity of the lines to mosquitoes point towards a decreased infectivity of the drug-selected lines as compared to the ancestral, reference one. We discuss the potential implication of these results on the spread of artesunate resistance in the field.

evolutionary biology↗

bioRxiv2020

Gene regulation of the avian malaria parasite Plasmodium relictum, during the different stages within the mosquito vector

The malaria parasite Plasmodium relictum is one of the most widespread species of avian malaria. As is the case in its human counterparts, bird Plasmodium undergoes a complex life cycle infecting two hosts: the arthropod vector and the vertebrate host. In this study, we examine the transcriptome of P. relictum (SGS1) during crucial timepoints within its natural vector, Culex pipiens quinquefasciatus. Differential gene-expression analyses identified genes linked to the parasites life-stages at: i) a few minutes after the blood meal is ingested, ii) during peak oocyst production phase, iii) during peak sporozoite phase and iv) during the late-stages of the infection. A large amount of genes coding for functions linked to host-immune invasion and multifunctional genes was active throughout the infection cycle. One gene associated with a conserved Plasmodium membrane protein with unknown function was upregulated throughout the parasite development in the vector, suggesting an important role in the successful completion of the sporogonic cycle. Transcript annotation further revealed novel genes, which were significantly differentially expressed during the infection in the vector as well as upregulation of reticulocyte-binding proteins, which raises the possibility of the multifunctionality of these RBPs. We establish the existence of highly stage-specific pathways being overexpressed during the infection. This first study of gene-expression of a non-human Plasmodium species in its natural vector provides a comprehensive insight into the molecular mechanisms of the common avian malaria parasite P. relictum and provides essential information on the evolutionary diversity in gene regulation of the Plasmodiums vector stages.

evolutionary biology↗

bioRxiv2020

The transmission-blocking effects antimalarial drugs revisited: mosquito fitness costs and sporontocidal effects of artesunate and sulfadoxine-pyrimethamine

Assays used to evaluate the transmission-blocking activity of antimalarial drugs are largely focused on their potential to inhibit or reduce the infectivity of gametocytes, the blood stages of the parasite that are responsible for the onward transmission to the mosquito vector. For this purpose, the drug is administered concomitantly with the gametocyte-infected blood, and the results are evaluated as the % reduction in the number of oocysts in the mosquito midgut. We report the results of a series of experiments that explore the transmission blocking potential of two key antimalarial drugs, artesunate (AS) and sulfadoxine-pyrimethamine (SP), when administered to mosquitoes already infected from a previous blood meal. For this purpose, uninfected mosquitoes and mosquitoes carrying a 6-day old Plasmodium relictum infection (early oocyst stages) are allowed to feed either on a drug-treated or an untreated host in a fully factorial experiment. This protocol allows us to bypass the gametocyte stages and establish whether the drugs are able to arrest the ongoing development of oocysts and sporozoites, as would be the case when a mosquito takes a post-infection treated blood meal. In a separate experiment, we also explore whether a drug-treated blood meal impacts key life history traits of the mosquito relevant for transmission, and if this depends on their infection status. Our results show that feeding on an AS- or SP-treated host has no epidemiologically relevant effects on the fitness of infected or uninfected mosquitoes. In contrast, when infected mosquitoes feed on an SP-treated host, we observe both a significant increase in the number of oocysts in the midgut, and a drastic decrease in both sporozoite prevalence (-30%) and burden (-80%) compared to the untreated controls. We discuss the potential mechanisms underlying these seemingly contradictory results and contend that, provided the results are translatable to human malaria, the potential epidemiological and evolutionary consequences of the current preventive use of SP in malaria-endemic countries could be substantial.

evolutionary biology↗

bioRxiv2020

Last-come, best served? Mosquito biting order and Plasmodium transmission

A pervasive characteristic of malaria parasite infection in mosquito vector populations is their tendency to be overdispersed. Understanding the mechanisms underlying the overdispersed distribution of parasites is of key importance as it may drastically impact the transmission dynamics of the pathogen. The small fraction of heavily infected individuals might serve as superspreaders and cause a disproportionate number of subsequent infections. Although multiple factors ranging from environmental stochasticity to inter-individual heterogeneity may explain parasite overdispersion, Plasmodium infection has also been observed to be highly overdispersed in inbred mosquito population maintained under standardized laboratory conditions, suggesting that other mechanisms may be at play. Here, we show that the aggregated distribution of Plasmodium within mosquito vectors is partially explained by a temporal heterogeneity in parasite infectivity triggered by the bites of blood-feeding mosquitoes. Several experimental blocks carried out with three different Plasmodium isolates have consistently shown that the transmission of the parasite increases progressively with the order of mosquito bites. Surprisingly the increase in transmission is not associated with an increase in Plasmodium replication rate or higher investment in the production of the transmissible stage (gametocyte). Adjustment of the physiological state of the gametocytes could be, however, an adaptive strategy to respond promptly to mosquito bites. Overall our data show that malaria parasite appears to be able to respond to the bites of mosquitoes to increase its own transmission at a much faster pace than initially thought (hours rather than days). Further work needs to be carried out to elucidate whether these two strategies are complementary and, particularly, what are their respective underlaying mechanisms. Understanding the processes underlying the temporal fluctuations in Plasmodium infectivity throughout vertebrate host-to-mosquito transmission is essential and could lead to the development of new approaches to control malaria transmission. Author summaryPlasmodium parasites are known for being the etiological agents of malaria and for the devastating effects they cause on human populations. A pervasive characteristic of Plasmodium infection is their tendency to be overdispersed in mosquito vector populations: the majority of mosquitoes tend to harbour few or no parasites while a few individuals harbor the vast majority of the parasite population. Understanding the mechanisms underlying Plasmodium overdispersed distribution is of key importance as it may drastically impact the transmission dynamics of the pathogen. Here, we show that the aggregated distribution of Plasmodium parasites within mosquito vectors is partially explained by a temporal heterogeneity in Plasmodium infectivity triggered by the bites of blood-feeding mosquitoes. In other words, mosquitoes that bite at the beginning of a 3h feeding session have significantly fewer parasites than those that bite towards the end. Malaria parasite is therefore capable of responding to the bites of mosquitoes to increase its own transmission at a much faster pace than thought (hours rather than days). Understanding the processes underlying the temporal fluctuations in Plasmodium infectivity throughout vertebrate host-to-mosquito transmission is essential and could lead to the development of new approaches to control malaria transmission.

microbiology↗

bioRxiv2018

Timing malaria transmission with mosquito fluctuations

Temporal variations in the activity of arthropod vectors can dramatically affect the epidemiology and evolution of vector-borne pathogens. Here we explore the \"Hawking hypothesis\" stating that these pathogens may evolve the ability to time investment in transmission to match the activity of their vectors. First, we use a theoretical model to identify the conditions promoting the evolution of time-varying transmission strategies in pathogens. Second, we experimentally test the \"Hawking hypothesis\" by monitoring the within-host dynamics of Plasmodium relictum throughout the acute and the chronic phases of the bird infection. To explore the periodicity in the host parasite density, we develop a new methodology to correct for non-stationarities in the host parasitaemia. We detect a periodic increase of parasitaemia and mosquito infection in the late afternoon that coincides with an increase in the biting activity of its natural vector. We also detect a positive effect of mosquito bites on Plasmodium replication in the birds both in the acute and in the chronic phases of the infection. This study highlights that Plasmodium parasites use two different strategies to increase the match between transmission potential and vector availability. We discuss the adaptive nature of these unconditional and plastic transmission strategies with respect to the time-scale and the predictability of the fluctuations in the activity of the vector.\n\nImpact SummarySeasonal and daily fluctuations in the environment affect the abundance and the activity of vectors and may therefore have profound consequences on the transmission of infectious diseases. Here we show that, in accord with evolutionary theory, malaria parasites have evolved two different and complementary strategies to cope with fluctuations in mosquito availability. First, Plasmodium relictum adopts an unconditional strategy whereby within-host parasitaemia and mosquito infection increases in the afternoon and in the evening, when its vector, the Culex pipiens mosquito, is most active. Second, we find evidence for a plastic strategy allowing the parasitaemia to rapidly increase after exposure to mosquito bites.

evolutionary biology↗

bioRxiv2016

Complete avian malaria parasite genomes reveal host-specific parasite evolution in birds and mammals

Avian malaria parasites are prevalent around the world, and infect a wide diversity of bird species. Here we report the sequencing and analysis of high quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum. We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species and using amino acid divergence between species, we estimate the avian and mammalian-infective lineages diverged in the order of 10 million years ago. Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing P. falciparum and P. vivax - the species with the greatest impact on human health. From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion related genes are evolving. The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family. We also identify an expansion of reticulocyte binding protein homologs in P. relictum and within these proteins, we detect distinct regions that are specific to non-human primate, humans, rodent and avian hosts. For the first time in the Plasmodium lineage we find evidence of transposable elements, including several hundred fragments of LTR-retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum.

genomics↗