Biology subjects

Seixas, E.

Publications and source records attributed to Seixas, E..

5 recordsLinked to original sources

bioRxiv2026

Pervasive bacterial and prophage hybridization during chronic gut inflammation

Inflammatory bowel diseases (IBD) are modulated by microbiota composition, host genetics, and environmental factors1. Humans and other mammals are colonized by multiple strains of Escherichia coli, a species that expands in abundance in IBD patients2. The state of chronic inflammation characteristic of IBD is expected to intensify selective pressures on the gut microbial community, leading to distinct adaptive trajectories among its constituents. Here we couple in vivo experimental evolution with short- and long-read sequencing to test this hypothesis at the level of mutation and horizontal gene transfer (HGT). By colonizing IL10KO mice, a model of IBD3, and healthy wild-type mice with two strains of E. coli, we show that the tempo and mode of evolution are strain-specific and strongly shaped by host inflammatory status. Unique mutations associate with host inflammatory status independently of microbiota composition, and rates of transfer are diagnostic of chronic inflammation. Extensive transduction events occur in the inflamed gut, giving rise to hybrid clones that form a new genetic lineage, one that becomes dominant in this disease context. The high levels of recombination between prophages uncovered here point to a critical role of HGT and viral evolution in IBD.

microbiology↗

bioRxiv2023

Massive lateral gene transfer under strain coexistence in the gut

Mammals are colonized by multiple strains of Escherichia coli, yet how such strain coexistence affects their tempo and mode of evolution is poorly understood. Here, by following the colonization of two phylogenetic distinct strains of E. coli in the mouse gut, we find a strain-specific mode of evolution and a remarkable level of gene transfer between strains. In the same host, despite accumulating mutations at the same rate, one strain evolves by diversifying selection and the other by directional selection, and a rich dynamics of bacteriophage and plasmid transfer is found. Our results provide support for an important role of lateral transduction in the mammalian gut.

evolutionary 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↗

bioRxiv2019

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

Synergy of resistance and disease tolerance mechanisms is necessary for an effective immune response leading to survival and return to homeostasis when an organism is challenged by infection. Antibiotics are used for their resistance enhancement capabilities by decreasing pathogen load, but several classes have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here we report that tetracycline antibiotics, a class of ribosome-targeting drugs, robustly protects against sepsis by inducing disease tolerance, independently from their direct antibiotic properties. Mechanistically, we find that mitochondrial inhibition of protein synthesis perturbs the electron transfer chain and leads to improved damage repair in the lung and fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a partial and acute deletion of CRIF1 in the liver, a critical mitoribosomal component for protein synthesis, we find that mice are protected against bacterial sepsis, an observation which is phenocopied by the transient inhibition of complex I of ETC by phenformin. Together, we demonstrate that ribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a novel mechanism for the induction of disease tolerance.

immunology↗

bioRxiv2019

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis

Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth-differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15 and that Gdf15-deficient animals are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.

immunology↗