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International audience; Meriones shawi (M.shawi) is the main reservoir host for zoonotic cutaneous leishmaniasis (ZCL) in Central Tunisia. The incorporation of environmental and climatic effects on the spread of ZCL in M. shawi remains difficult. This study presents an agent-based model (ABM) to overcome these difficulties and examine the impact of environment (i.e. vegetation cover) and climate (i.e. temperature) on M. shawi movement and prevalence. The model simulation considers two agent types: rodent agent and field unit agent. We tested the model according to two types of rodent movement: random and thoughtful. We integrated time dependent normalized difference vegetation index (NDVI) in order to test the land cover effects on rodent movement and ZCL transmission. The results confirmed that the spread of the disease depends on rodent movement. We observed that prevalence and distribution are the closest to field data when the vegetation cover is highest and that rodents go for thoughtful movement. In addition, we found that the nature of movement (random or thoughtful) and prevalence depends strongly on minimum food detection.

International audience; We investigate the existence and stability of sexual strategies (sequential hermaphrodite, successive hermaphrodite or gonochore) at a proximate level. To accomplish this, we constructed and analyzed a general dynamical game model structured by size and sex. Our main objective is to study how costs of changing sex and of sexual competition should shape the sexual behavior of a hermaphrodite. We prove that, at the proximate level, size alone is insufficient to explain the tendency for a pair of prospective copulants to elect the male sexual role by virtue of the disparity in the energetic costs of eggs and sperm. In fact, we show that the stability of sequential vs. simultaneous hermaphrodite depends on sex change costs, while the stability of protandrous vs. protogynous strategies depends on competition cost.

A major challenge in ecological modeling of complex living system, is the integration of different models that describe the same phenomenon at different levels (physiological and ecological levels). The multi-agent paradigm provides an intuitive approach to model and simulate individual metabolism (Dynamic Energy Budget (DEB) model) and sexual behavior (Sex allocation model) and connect them to population-level proprieties. In this work, we model the energetic and sexual behavior of hermaphrodite species to determine the optimal size of sex change. For this purpose, we consider population dynamics and individuals evolutionary traits. Sex change size is seen as an emerging traits from both the set of intra-individual physiological traits, and inter-individual interactions. We develop an evolutionary individual-based model implementing these two models with a simple genetic algorithm to determine the optimal sex change size. The model description follows the ODD (Overview, Design concepts, Details) protocol, it is simulated with NetLogo platform and it is parametrized for Dusky grouper (Epinephelus marginatus). For this hermaphrodite species, both growth and maturation predicted by the model fit well with field observations.

Background Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts. Methodology/Principal Findings We report in this study a comprehensive analysis of miRNA expression profiles in L. major-infected human primary macrophages of three healthy donors assessed at different time-points post-infection (three to 24 h). We show that expression of 64 out of 365 analyzed miRNAs was consistently deregulated upon infection with the same trends in all donors. Among these, several are known to be induced by TLR-dependent responses. GO enrichment analysis of experimentally validated miRNA-targeted genes revealed that several pathways and molecular functions were disturbed upon parasite infection. Finally, following parasite infection, miR-210 abundance was enhanced in HIF-1α-dependent manner, though it did not contribute to inhibiting anti-apoptotic pathways through pro-apoptotic caspase-3 regulation. Conclusions/Significance Our data suggest that alteration in miRNA levels likely plays an important role in regulating macrophage functions following L. major infection. These results could contribute to better understanding of the dynamics of gene expression in host cells during leishmaniasis., Author Summary Leishmania parasites belong to different species, each one characterized by specific vectors and reservoirs, and causes cutaneous or visceral disease(s) of variable clinical presentation and severity. In its mammalian host, the parasite is an obligate intracellular pathogen infecting the monocyte/macrophage lineage. Leishmania have developed ambiguous relationships with macrophages. Indeed, these cells are the shelter of invading parasites, where they will grow and eventually will reside in a silent state for life. But macrophages are also the cells that participate, through the induction of several pro-inflammatory mediators and antigen presentation, to shape the host immune response and ultimately kill the invader. To subvert these anti-parasite responses, Leishmania manipulate the host machinery for their own differentiation and survival. We aimed to evaluate the impact of L. major (the causative agent of zoonotic cutaneous leishmaniasis) infection on deregulation of non-coding miRNAs, a class of important regulators of gene expression. Our results revealed the implication of several miRNAs on macrophage fate upon parasite infection through regulation of different pathways, including cell death. Our findings provided a new insight for understanding mechanisms governing this miRNA deregulation by parasite infection and will help to provide clues for the development of control strategies for this disease.

We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different times after infection with promastigotes of the protozoan parasite Leishmania major. Ingenuity Pathway Analysis revealed that the macrophage metabolic pathways including carbohydrate and lipid metabolisms were among the most altered pathways at later time points of infection. Indeed, L. major promastiogtes induced increased mRNA levels of the glucose transporter and almost all of the genes associated with glycolysis and lactate dehydrogenase, suggesting a shift to anaerobic glycolysis. On the other hand, L. major promastigotes enhanced the expression of scavenger receptors involved in the uptake of Low-Density Lipoprotein (LDL), inhibited the expression of genes coding for proteins regulating cholesterol efflux, and induced the synthesis of triacylglycerides. These data suggested that Leishmania infection disturbs cholesterol and triglycerides homeostasis and may lead to cholesterol accumulation and foam cell formation. Using Filipin and Bodipy staining, we showed cholesterol and triglycerides accumulation in infected macrophages. Moreover, Bodipy-positive lipid droplets accumulated in close proximity to parasitophorous vacuoles, suggesting that intracellular L. major may take advantage of these organelles as high-energy substrate sources. While the effect of infection on cholesterol accumulation and lipid droplet formation was independent on parasite development, our data indicate that anaerobic glycolysis is actively induced by L. major during the establishment of infection., Author Summary Leishmania are obligated intracellular pathogens that develop almost exclusively in macrophages. Experimental leishmaniasis in mice is one of the most extensively studied models of intracellular infections both at the level of the parasite and host immune responses. We took advantage of Balb/c mice model to investigate gene expression profile through Affymetrix oligonucleotide arrays. In order to have a general and dynamic picture of the complex biological events that are acting in the context of Leishmania intracellular parasitism, we investigated the mouse macrophage response to initial invasion of L. major over a time course that extended from one to 24 hours post-infection. Our results reveal the alteration of several biological processes and metabolic changes. Indeed, similarly to different other pathogens, Leishmania induces cholesterol accumulation and foam cell formation that have been confirmed by confocal microscopy experiments. Whether Leishmania parasites take advantage of this high-energy source is now under investigation. Our findings provided further understandings in host responses to Leishmania infection.

29th Conference of the French-Speaking-Society-for-Theoretical-Biology, St Flour, FRANCE, jun4-17, 2009; International audience; Dusky groupers (Epinephelus marginatus) are characterized by a complex sex allocation strategies and overexploitation of bigger individuals. We developed an individual based model to investigate the long-term effects of density dependence on grouper population dynamics and to analyze the variabilities of extinction probabilities as a result of interacting mortalities at different life stages. We conduct several simulations with different forms of sex allocation functions and different combinations of mortality rates. The model was parametrized using data on dusky grouper populations from the literature. The most important insights produced by this simulation study are that density dependence of sex allocation is an evolutionarily stable strategy, increases the population biomass, mitigates the effect of the removal of large male and indicates a need for protection of females and flexible stages.

This chapter reports a variety of molecular biology informatics and mathematical methods that model the cell response to pathogens. The authors first outline the main steps of the immune response, then list the high throughput biotechnologies, generating a wealth of information on the infected cell and some of the immune-related databases; and finally explain how to extract meaningful information from these sources. The modelling aspect is divided into modelling molecular interaction and regulatory networks, through dynamic Boolean and Bayesian models, and modelling biochemical networks and regulatory networks, through Differential/Difference Equations. The interdisciplinary approach explains how to construct a model that mimics the cell’s dynamics and can predict the evolution and the outcome of infection.

Background Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence but also on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes including Leishmania. Results Here we compared the transcriptional signatures of resistant (C57BL/6) and susceptible (BALB/c) mouse bone marrow-derived macrophages in response to Leishmania major (L. major) promastigotes infection. Microarray results were first analyzed for significant pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG) database. The analysis revealed that a large set of the shared genes is involved in the immune response and that difference in the expression level of some chemokines and chemokine receptors could partially explain differences in resistance. We next focused on up-regulated genes unique to either BALB/c or C57BL/6 derived macrophages and identified, using KEGG database, signal transduction pathways among the most relevant pathways unique to both susceptible and resistant derived macrophages. Indeed, genes unique to C57BL/6 BMdMs were associated with target of rapamycin (mTOR) signaling pathway while a range of genes unique to BALB/c BMdMs, belong to p53 signaling pathway. We next investigated whether, in a given mice strain derived macrophages, the different up-regulated unique genes could be coordinately regulated. Using GeneMapp Cytoscape, we showed that the induced genes unique to BALB/c or C57BL/6 BMdMs are interconnected. Finally, we examined whether the induced pathways unique to BALB/c derived macrophages interfere with the ones unique to C57BL/6 derived macrophages. Protein-protein interaction analysis using String database highlights the existence of a cross-talk between p53 and mTOR signaling pathways respectively specific to susceptible and resistant BMdMs. Conclusions Taken together our results suggest that strains specific pathogenesis may be due to a difference in the magnitude of the same pathways and/or to differentially expressed pathways in the two mouse strains derived macrophages. We identify signal transduction pathways among the most relevant pathways modulated by L. major infection, unique to BALB/c and C57BL/6 BMdM and postulate that the interplay between these potentially interconnected pathways could direct the macrophage response toward a given phenotype.