Biology subjects

Giraud-Gatineau, A.

Publications and source records attributed to Giraud-Gatineau, A..

6 recordsLinked to original sources

bioRxiv2026

Host adaptation drives genome evolution and virulence diversification in a bacterial zoonotic pathogen

Understanding how zoonotic pathogens diversify across reservoir hosts remains a central question in evolutionary biology and infectious disease research. Here, we address this challenge using Leptospira interrogans, a globally distributed bacterial pathogen with an extremely wide range of animal reservoirs, as a model. After defining 13 distinct genogroups that largely align with serogroups, we selected the strongly host-adapted rodent-associated lineage, which is more frequently associated with fatal outcomes in patients, and the cattle-associated lineage for further analysis. A comprehensive approach integrating multi-omics analyses and host-specific infection assays showed that these two genogroups have followed distinct evolutionary trajectories associated with host specialization. Genomics demonstrated that specialized genogroups are genetically less diverse, characterized by divergence in membrane and signaling genes, and by the acquisition of host-adaptive functions. Changes in gene expression and protein production revealed distinct regulatory programs, predominantly affecting virulence pathways in rodent-borne lineage and stress responses in cattle-borne lineage. Consistently, rodent-borne lineage causes greater disruption of human epithelial barrier integrity and elicits an attenuated host-dependent macrophage inflammatory response relative to cattle-borne lineage. Collectively, these findings reveal distinct host-adaptive strategies and remarkable evolutionary plasticity in a major zoonotic bacterium, highlighting the central role of intraspecies heterogeneity in shaping host specialization.

microbiology↗

bioRxiv2025

In Vivo Dual RNA-Seq uncovers key toxin-like effectors of epithelial barrier disruption and tissue colonization by an extracellular bacterial pathogen

Disruption of host cell barriers is a fundamental strategy enabling pathogens to establish a paracellular infection. Using dual RNA-Seq, we determined the in vivo host-pathogen transcriptomic landscape upon infection by the extracellular pathogen Leptospira interrogans and uncovered a novel mechanism of cell-cell junction disruption. We demonstrated that, upon infection, an increase in intracellular calcium triggered tight junction destabilization, by activating the calmodulin and myosin light chain kinase signalization. We identified two novel bacterial effectors of the Virulence-Modifying (VM) proteins family, structurally related to toxin-like proteins, that promoted modulation of calcium homeostasis and disruption of cell-cell junctions, thereby allowing Leptospira translocation across epithelium barriers, tissue colonization and pathogenicity. Furthermore, we demonstrated that at least one of these VM proteins was internalized inside host cells. Altogether, these findings reveal a unique strategy by which an extracellular pathogen secretes toxin-like proteins to exploit host calcium signaling for breaching epithelial barriers.

microbiology↗

bioRxiv2025

DMEM and EMEM are suitable surrogate media to mimic host environment and expand leptospiral pathogenesis studies using in vitro tools

Pathogenic Leptospira species can survive and thrive in a wide range of environments. Distinct environments expose the bacteria to different temperatures, osmolarities, and amounts and sources of nutrition. However, leptospires are mostly cultured, in a laboratory setting under in vitro conditions that do not reflect natural environments. This constraint on laboratory cultures limits the applicability of in vitro studies to the understanding of even simple pathogenic processes. Here we report, investigate, and identify a medium and conditions that mimic the host environment during leptospirosis infection, expanding the available in vitro tools to evaluate leptospiral pathogenesis. We quantified genome-wide gene expression of pathogenic Leptospira interrogans cultured in different in vitro media compositions (EMJH, DMEM, EMEM, and HAN). Using EMJH as standard, we compared gene expression in these compositions to genome-wide gene expression gathered in a host environment: whole blood (WB) of hamsters after infection with pathogenic leptospires. Leptospires cultured in DMEM and EMEM media shared 40% and 47% of all differentially expressed genes (DEGs) of leptospires present within WB (FDR<0.01), while leptospires cultured in HAN media only shared 20% of DEGs with those from WB. Furthermore, gene and pathway expression of leptospires cultured on DMEM and EMEM media exhibited a better correlation with leptospires grown in WB, including promoting expression of a similar leptospiral lipid A profile to the one identified directly in host tissues. Taken together, these results indicate that commercial cell-culture media EMEM or DMEM are better surrogates for in vivo pathogenic studies than EMJH or HAN media in Leptospira. These alternative culture conditions, using media that are a standard supply worldwide, provide a reproducible and cost-effective approach that can accelerate research investigation and reduce the number of animal infections necessary for basic research of leptospirosis.

microbiology↗

bioRxiv2024

Evolutionary insights into the emergence of virulent Leptospira spirochetes

Pathogenic Leptospira are spirochete bacteria which cause leptospirosis, a re-emerging zoonotic disease of global importance. Here, we use a recently described lineage of environmental-adapted leptospires, which are evolutionarily the closest relatives of the highly virulent Leptospira species, to explore the key phenotypic traits and genetic determinants of Leptospira virulence. Through a comprehensive approach integrating phylogenomic comparisons with in vitro and in vivo phenotyping studies, we show that the evolution towards pathogenicity is associated with both a decrease of the ability to survive in the environment and the acquisition of strategies that enable successful host colonization. This includes the evasion of the human complement system and the adaptations to avoid activation of the innate immune cells. Moreover, our analysis reveals specific genetic determinants that have undergone positive selection during the course of evolution in Leptospira, contributing directly to virulence and host adaptation as demonstrated by gain-of-function and knock-down studies. Taken together, our findings define a new vision on Leptospira pathogenicity, identifying virulence attributes associated with clinically relevant species, and provide insights into the evolution and emergence of these life-threatening pathogens. AUTHOR SUMMARYLeptospira is a highly heterogeneous bacterial genus and leptospires are ubiquitous bacteria found as free-living saprophytes or as pathogens that can cause disseminated infections, from asymptomatic carriage in rats to lethal acute infection in both humans and animals. Leptospirosis is thus causing over one million cases and nearly 60,000 deaths annually. Despite leptospirosis being a re-emerging zoonosis, little is known about the ability of the etiologic agent to adapt to different hosts and cause disease. Here, combining genome analysis and phenotyping studies of representative species and mutant strains, we show that only a small group of species have the ability to evade the host immune system and cause disease. In addition, our findings provide key insight into the emergence of pathogens from a saprophytic ancestor through events of gene gain and genome reduction.

microbiology↗

bioRxiv2023

An oxadiazole-based compound potentiates anti- tuberculosis treatment by increasing host resistance via zinc poisoning

Anti-tuberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multi-resistant strains of Mycobacterium tuberculosis are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high content imaging, we identified novel 1,2,4-oxadiazole-based compounds, that allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, M. tuberculosis became even more sensitive to anti-tuberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.

microbiology↗

bioRxiv2019

The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the hosts immune system. Here we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed macrophages into potent bactericidal phagocytes. We found that 1,495 genes were differentially expressed in M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of genes involved in metabolism, lysosome biogenesis and activation. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including nitric oxide production, phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB (TFEB), involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.

immunology↗