Biology subjects

Finlay, B. B.

Publications and source records attributed to Finlay, B. B..

10 recordsLinked to original sources

bioRxiv2026

Vancomycin promotes key microbiota-pathogen interactions and removes protective bottlenecks to enteric infection

Antibiotic exposure disrupts enteric pathogen colonization resistance, yet how antibiotics reshape pathogen population dynamics, infection bottlenecks, and strain-level heterogeneity in the gut remains poorly understood. Here, we combine high-resolution pathogen barcoding, transcriptomic, and metabolomic analyses to quantify how short-term vancomycin perturbation alters infection ecology in vivo. We use Citrobacter rodentium as a model for human infection by pathogenic Escherichia coli-an antimicrobial resistance priority group-to demonstrate that just two days of vancomycin pre-treatment profoundly reshapes infection trajectories, driving rapid, global gut colonization, a dramatic increase in pathogen founding population size, and preservation of strain diversity across intestinal sites. Notably, vancomycin eliminated the hallmark heterogeneity of C. rodentium infection, resulting in fully reproducible colonization across hosts. Population-level analysis revealed that antibiotic treatment relaxes competitive constraints both with the resident microbiota and among clonal pathogen lineages, allowing early-established founders to persist and expand. Despite accelerated pathogen engraftment and tissue pathology, transcriptomic analysis revealed reduced virulence gene expression. Instead, antibiotic-induced metabolic restructuring of the gut created permissive conditions for pathogen expansion. Interactions with a vancomycin-altered microbiota, dominated by Akkermansia and Bacteroides, further promoted nutrient cross-feeding and influenced epithelial attachment. Together, we illustrate how short-term antibiotic exposure reshapes enteric infection by removing ecological bottlenecks that normally constrain strain diversity and infection outcomes. These findings have implications for antibiotic use, antimicrobial resistance transmission, and therapeutic strategies that rely on competition-driven dynamics, such as strain replacement.

microbiology↗

bioRxiv2026

Lithocholic acid modulates the growth of butyrate-producing bacteria and is decreased in the feces of stunted children

Bile acids modulate the intestinal microbiota and serve as key signaling molecules in host physiology. Bile acid dysregulation has been implicated in nutritional and inflammatory diseases; however, data on the pool of bile acids present in stunted children or children suffering of environmental enteric dysfunction (EED) is limited, particularly in the upper intestinal compartment where disease phenotypes are most relevant. In this study, we performed a targeted metabolomics approach on 75 bile acids and their derivatives, including gastric and duodenal aspirates and fecal samples from almost 1000 children from two Sub-Saharan cities. We found that levels of secondary bile acids, especially lithocholic acid, are significantly lower in the feces of stunted and EED children, while ursocholic acid and its derivatives are significantly higher. Levels of primary and sulfated bile acids are also increased in the feces of children with EED. Microbiota sequencing revealed that high lithocholic acid levels are positively associated with butyrate-producing bacteria, while negatively associated with oral taxa like Streptococcus and Veillonella. In vitro tests on a panel of reference strains showed that oral bacteria bioaccumulate and are inhibited by a variety of bile acids, while lithocholic and chenodeoxycholic acids modulate the growth of several butyrate-producing bacteria. This effect was even stronger with tauro- or glycol-conjugated bile acids. Exposing stool-derived in vitro communities from children in Afribiota to these bile acids confirmed their positive impact on butyrate producers and negative effect on overgrowing oral taxa. Our findings suggest that secondary bile acids, reduced in stunting and EED, modulate the growth of butyrate-producing bacteria while suppressing harmful oral taxa, highlighting their potential as tools to modulate microbiota composition.

microbiology↗

bioRxiv2025

Enteropathogenic Escherichia coli manipulates the host exocyst complex to enhance pedestal formation

Enteropathogenic Escherichia coli (EPEC), a major cause of diarrheal disease, produces plasma membrane pedestals that promote colonization of host cells. Critical for pedestal formation is EPECs type III secretion system, which injects [~] 20 effector proteins into human cells. One of these effectors is Tir, which inserts into the host plasma membrane and stimulates the assembly of actin filaments essential for pedestal generation. To date, actin polymerization is the only host process known to contribute to pedestal formation. Here we report that EPEC co-opts the membrane trafficking pathway of polarized exocytosis, which acts together with actin polymerization to allow the efficient production of pedestals. Polarized exocytosis is mediated by the exocyst -- a human octameric complex that uses intracellular vesicles to expand the plasma membrane. We found that EPEC stimulated exocytosis at sites of pedestal formation in a manner dependent on the exocyst. The bacterial effector EspH recruited the exocyst and promoted exocytosis. Genetic inactivation of espH or RNA interference (RNAi)-induced depletion of exocyst components reduced both the frequency and size of pedestals. Additional RNAi experiments indicated that the exocyst is dispensable for actin filament assembly in pedestals. Co-depletion of components of the exocyst and the Arp2/3 complex showed that exocytosis and actin polymerization make additive contributions to pedestal formation. Collectively, these results indicate that exocyst-mediated expansion of the plasma membrane acts together with actin polymerization to optimize the generation of pedestals. IMPORTANCEEnteropathogenic E. coli (EPEC) induces the formation of host cell plasma membrane protrusions called "pedestals" that mediate tight adherence to intestinal epithelial cells. Substantial evidence indicates that the generation of pedestals requires bacterial-induced polymerization of the host cell actin cytoskeleton. However, it remains unknown if EPEC manipulates other human processes to augment the efficiency of pedestal generation. The significance of this research is to demonstrate that EPEC co-opts a second host process called polarized exocytosis to increase the frequency of pedestals and the size of these structures. EPEC induces exocytosis by using its effector protein EspH to recruit the human exocyst complex, which mediates the insertion of membrane at sites of bacterial attachment. Our results demonstrate EPECs ability to coordinate host membrane trafficking with cytoskeletal changes to enhance infection. Remarkably, EPEC shares this strategy with the intracellular bacterial pathogens Listeria monocytogenes and Shigella flexneri.

microbiology↗

bioRxiv2024

Metabolic conservation by protein quality control in Campylobacter jejuni underlies the antibiotic tolerance

Bacterial persistence enables survival during lethal antibiotic exposure and is implicated in recurrent infections, yet the physiology underlying bacterial persistence in many pathogens remains poorly defined. Here we show that exposure of Campylobacter jejuni to ampicillin or ciprofloxacin generates an antibiotic-persistent subpopulation. Rather than undergoing global metabolic shutdown, persister cells adopted a metabolically constrained state characterized by selective maintenance of oxidative phosphorylation and bioenergetic metabolism through coordinated proteostasis control. The ATP-dependent protease ClpP was essential for entry into this persistent state. Loss of ClpP disrupted proteostasis of the electron transport chain, specifically impaired bd-like terminal oxidase integrity, and reduced survival in vivo and in macrophages. These findings identify ClpP-dependent maintenance of redox and bioenergetic homeostasis as critical determinants of C. jejuni persistence and highlight metabolic remodeling as a defining feature of antibiotic tolerance. These insights may inform future therapeutic strategies aimed at disrupting persistence and improving antibiotic efficacy.

microbiology↗

bioRxiv2024

Pathogen and host adapt pH responses during enteric infection

Enteric pathogens navigate distinct regional micro-environments within the intestine which cue important adaptive behaviours. We investigated the response of Citrobacter rodentium, a model of human pathogenic Escherichia coli infection, to regional gastrointestinal pH. We found that small intestinal pH (4.4-4.8) triggered virulence gene expression and altered cell morphology, supporting initial intestinal attachment, while higher pH, representative of C. rodentiums replicative niches further along the intestine, supported pathogen growth. Gastric pH, a key barrier to intestinal colonization, caused significant accumulation of intra-bacterial reactive oxygen species, inhibiting growth of C. rodentium and related human pathogens. Within-host adaptation increased gastric acid survival, which may be due to a robust acid tolerance response induced at colonic pH. However, we also found that host gastric pH decreases post-infection, corresponding to increased serum gastrin levels and altered host expression of acid secretion-related genes. Similar responses following Salmonella infection may indicate a protective host response to limit further pathogen ingestion. Together, we highlight adaptive pH responses as an important component of host-pathogen co-evolution.

microbiology↗

bioRxiv2023

Quorum Sensing Modulates Bacterial Virulence and Colonization Dynamics During an Enteric Infection

Quorum Sensing (QS) is a form of cell-to-cell communication that enables bacteria to modify behaviour according to their population density. While QS has been proposed as a potential intervention against pathogen infection, QS-mediated communication within the mammalian digestive tract remains understudied. Using an LC-MS/MS approach, we discovered that Citrobacter rodentium, a natural murine pathogen used to model human infection by pathogenic Escherichia coli, utilizes the CroIR system to produce three QS-molecules. We then profiled their accumulation both in vitro and across different gastrointestinal sites over the course of infection. Importantly, we found that in the absence of QS capabilities the virulence of C. rodentium is enhanced. This highlights the role of QS as an effective mechanism to regulate virulence according to the pathogens spatio-temporal context to optimize colonization and transmission success. These results also demonstrate that inhibiting QS may not always be an effective strategy for the control of virulence.

microbiology↗

bioRxiv2021

Dual perspective proteomics infectome profiling discovers Salmonella type III secretion system effector functions in macrophages

Intracellular bacterial pathogens have evolved sophisticated infection strategies, including the release and secretion of virulence factors to interfere with host cell functions and to perturb immune responses. For Salmonella enterica serovar Typhimurium (S. Typhimurium), the type III secretion systems encoded on Salmonella pathogenicity islands (SPI) 1 and 2 mediates invasion of the bacterium into innate immune cells and regulates bacterial replication and survival within the hostile environment of the host, respectively. Here, we explore the temporal and strain-specific dual perspective response of both the host and pathogen during cellular infection via quantitative proteomics. We report time- and pathogenicity island-specific expression and secretion of infection-associated proteins (i.e., SL1344_1263, SL1344_3112, SL1344_1563, and YnhG) and regulated immune response proteins in macrophage, including Cd86, Cd40, Casp4, C3, IL-1, and Cd69). Through intracellular macrophage and in vivo murine models of infection, we reveal a role in virulence for three of the bacterial proteins (SL1344_1263, SL1344_1563, and YnhG), defining their importance as novel T3SS effectors. We characterize the temporal intra- and extracellular production of the effectors and identify their interaction networks in host cells, representing inhibitory and stimulatory pathways mounted by invading bacterial pathogens. Author SummaryThe relationship between a host and pathogen is intricate, and regulation of the host immune response correlates with the progressive timing of infection and tailored responses to the pathogen. Relying on detection and quantification of protein-level changes using mass spectrometry-based proteomics, we explore the production of known and novel effectors by Salmonella during intracellular survival within macrophage. Our results portray a role for these effectors in bacterial virulence using an in vivo murine model of infection, and we define a dynamic network of interaction between the effectors and host proteins. These interactions reveal opportunity for drug design to disrupt modulation of the host by the invading bacterium as a new strategy for combatting infection. Our approach is dynamic and universal, with the power to alter therapeutic discovery against infectious diseases.

microbiology↗

bioRxiv2021

Cervical Squamous Intraepithelial Lesions are Associated with Changes in the Vaginal Microbiota of Mexican Women

Cervical cancer is an important health concern worldwide and is one of the leading causes of deaths in Mexican women. Previous studies have shown changes in the female genital tract microbe community related to Human Papillomavirus (HPV) infection and cervical cancer, yet this link remains unexplored in many human populations. This study evaluated the vaginal bacterial community among Mexican women with pre-cancerous Squamous Intraepithelial Lesions (SIL). We sequenced the V3 region of the 16S rRNA gene (Illumina Miseq) in cervical samples from 300 Mexican women, including 157 patients with SIL, most of which were HPV positive, and 143 healthy women without HPV infection or SIL. Beta-diversity analysis showed that 14.6% of the variance in vaginal bacterial community structure is related to the presence of SIL. Presence of SIL was also associated with a higher species richness (Chao 1). MaAsLiN analysis yielded independent associations between SIL/HPV status and an increase in the relative abundance Brachybacterium conglomeratum, as well as a decrease in Sphingobium yanoikuyae and Lactobacillus spp. We also identified independent associations between HPV-16, the most common HPV subtype linked to SIL, and Brachybacterium conglomeratum. Our work indicates that the presence of SIL and HPV infection is associated with important changes in the vaginal microbiome, some of which may be specific to this human population. IMPORTANCEHPV plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating involvement of other factors. Vaginal microbiota is an important factor in controlling infections caused by HPV and depending on its composition it can modulate the microenvironment in vaginal mucosa against viral infection. Ethnic and sociodemographic factors influence differences in vaginal microbiome composition, which underlies the dysbiotic patterns linked to HPV infection and cervical cancer across different women populations. Here, we provide evidence for associations between vaginal microbiota patterns and HPV infection, linked to ethnic and sociodemographic factor. To our knowledge, this is the first report of Brevibacterium aureum and Brachybacterium conglomeratum species linked to HPV infection or SIL.

microbiology↗

bioRxiv2020

Accurate identification and quantification of commensal microbiota bound by host immunoglobulins

BackgroundIdentifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins. ResultsUsing germ-free and Rag1-/- mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data from in vivo disease models. ConclusionsWe provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types.

bioinformatics↗

bioRxiv2019

Exposure to parasitic protists and helminths changes the intestinal community structure of bacterial microbiota but not of eukaryotes in a cohort of mother-child binomial from a semi-rural setting in Mexico

Around 3.5 billion people are colonized by intestinal parasites worldwide. Intestinal parasitic eukaryotes interact not only with the host, but also with the intestinal microbiota. In this work, we studied the relationship between the presence of multiple enteric parasites and the community structure of the bacterial and eukaryote intestinal microbiota in an asymptomatic cohort of mother-child binomials from a semi-rural community in Mexico. The intestinal parasites identified were Blastocystis hominis, Entamoeba histolytica/dispar, Endolimax nana, Chilomastix mesnili, Iodamoeba butshlii, Entamoeba coli, Hymenolepis nana and Ascaris lumbricoides. We sequenced bacterial 16S rDNA and eukaryotic 18S rDNA in fecal samples of 46 mothers and their respective children, with ages ranging from two to twenty months. Although we did not find significant alpha-diversity changes, we found a significant effect of parasite exposure on bacterial beta-diversity, which explained between 5.2% and 15.0% of the variation of the bacterial community structure. Additionally, exposure to parasites was associated with significant changes in relative abundances of bacterial taxa, characterized by increases in the Clostridia and decreased Actinobacteria and Bacteroidia abundances. There were no significant changes of intestinal microeukaryote abundances associated with parasite exposure. However, we found several significant positive correlations between intestinal bacteria and eukaryotes, including co-occurrence of the fungi Candida tropicalis with Bacteroides and Actinomyces, and Saccharomycetales with Bifidobacterium and Prevotella copri. These bacterial community structure changes associated with parasite exposure imply effects on microbial metabolic routes, host nutrient uptake abilities and intestinal immunity regulation in host-parasite interactions.\n\nIMPORTANCEThe impact of intestinal eukaryotes on the prokaryotic microbiome composition of asymptomatic carriers has not been extensively explored, especially in children and in hosts with multiple parasites. In this work, we studied the relationship between protist and helminth parasite colonization and intestinal microbiota structure in an asymptomatic population of mother-child binomials from the semi-rural community of Morelos in Mexico. We found that the presence of parasitic eukaryotes correlated with changes in the bacterial community structure in the intestinal microbiota in an age-dependent way. This was characterized by an increase of the relative abundance of the class Clostridia and the decrease of Actinobacteria and Bacteroidia. While there were no significant associations between the presence of parasites and microeukaryote community structure, we observed strong positive correlations between bacterial and eukaryote taxa, identifying novel relationships between prokaryotes and fungi, and reflecting the diet of the human population studied.

microbiology↗