Biology subjects

Aragon, V.

Publications and source records attributed to Aragon, V..

9 recordsLinked to original sources

bioRxiv2026

Genome-scale metabolic model atlas of the zoonotic pathogen Streptococcus suis

Streptococcus suis is a Gram-positive bacterium with a dual role as a commensal member of the porcine nasal microbiota and a pathogen causing systemic disease in pigs and humans. Mounting evidence suggests that metabolism is a key driver of S. suis pathogenicity. Given the species high genetic variability, we hypothesize that differences in metabolic networks could explain the diverse pathogenic phenotypes observed across different strains. To test this, we generated an atlas of over 3000 strain-specific and automatically curated genome-scale metabolic models that cover the breadth of pathogenic and commensal S. suis lineages. Using this model atlas, we performed the first species-level examination of metabolic traits in S. suis. Our simulations, supported by experimental validation, revealed three key insights. First, while metabolic traits are broadly conserved in S. suis, there are nevertheless lineage-dependent differences in amino acid auxotrophies and carbon utilization patterns that point towards distinct in vivo niches. Second, most strains are predicted to grow in different plausible in vivo environments regardless of their virulence phenotype, suggesting that metabolism is a weak barrier to systemic infection. Third, by systematically predicting reaction essentiality in more than 15 million reaction-strain-condition combinations, we identify a subset of 17 reactions, largely in nucleotide metabolism, that are conditionally essential in vivo and may serve as new targets for the development of new antimicrobials or vaccines. Overall, this study provides a valuable new resource for broadly examining S. suis metabolism and its role in pathogenicity.

Systems Biology↗

bioRxiv2025

SET-M33 peptide as a selective in vitro antimicrobial agent against the porcine respiratory pathogen Glaesserella parasuis

As we face the threat from bacterial pathogens that are resistant to many conventional antibiotics, many current research efforts focus on expanding our arsenal of antimicrobial compounds. However, identifying use cases in which such new antimicrobials can effectively target pathogens while minimizing collateral damage in the commensal microbiota remains a challenge. To tackle this challenge, we focused on one new antimicrobial, the synthetic antimicrobial peptide SET-M33, and examined its ability to target porcine respiratory pathogens and a collection of porcine commensal nasal microbiota members in vitro. Our experiments revealed three key results. First, there were large differences in SET-M33 sensitivity across the tested strains. In particular, pathogenic Glaesserella parasuis was highly sensitive to SET-M33 at concentrations that did not affect the growth of most commensal strains. Second, some of the tested commensal strains (i.e. Rothia nasimurium and Staphylococcus aureus) were able to inactivate SET-M33 during in vitro cultivation. Third, despite this potential for SET-M33 inactivation by commensal strains, SET-M33 was still able to selectively eliminate pathogenic G. parasuis from in vitro co-cultures that also contained R. nasimurium. Overall, this study highlights the substantial complexity that emerges from the interplay between antimicrobials, pathogens, and commensals, even within a comparatively simple in vitro system, and provides a template for identifying suitable use cases for newly developed antimicrobials.

microbiology↗

bioRxiv2025

δ-catenin haploinsufficiency is sufficient to alter behaviors and glutamatergic synapses in mice

{delta}-catenin (also known as CTNND2) functions as an anchor for the glutamatergic AMPA receptor (AMPARs) to regulate synaptic activity in excitatory synapses. Alteration in the gene coding {delta}-catenin has been implicated in many neurological disorders. Some of these genetic alterations exhibit a profound loss of {delta}-catenin functions in excitatory synapses. We have shown that {delta}-catenin deficiency induced by the homozygous {delta}-catenin knockout (KO) and autism-associated missense glycine 34 to serine (G34S) mutation significantly alters AMPAR-mediated synaptic activity in cortical neurons and disrupts social behavior in mice. Importantly, many genetic disorders are caused by haploinsufficiency. Indeed, {delta}-catenin haploinsufficiency contributes to severe autism and learning disabilities in humans. However, previous studies have used only homozygous {delta}-catenin deficiency models. Therefore, it is important to examine the effects of {delta}-catenin haploinsufficiency on animals behaviors and excitatory synapses. Here, we use heterozygous {delta}-catenin KO and G34S mice as a {delta}-catenin haploinsufficiency model to examine this idea. Multiple behavioral assays, a social behavior test, contextual fear conditioning, and an open field test, reveal that both {delta}-catenin KO and G34S haploinsufficiency significantly disrupt animals social behavior and fear learning and memory. Interestingly, only KO haploinsufficiency mice show anxiety-like behavior. A biochemical assay using brain extracts demonstrates that {delta}-catenin haploinsufficiency significantly affects the levels of synaptic {delta}-catenin and AMPARs. Our findings thus suggest that {delta}-catenin haploinsufficiency affects animals behaviors via altering glutamatergic synaptic activity.

neuroscience↗

bioRxiv2025

Genome editing of phylogenetically distinct bacteria using portable retron-mediated recombineering

Advanced genome editing technologies have enabled rapid and flexible rewriting of the Escherichia coli genome, benefiting fundamental biology and biomanufacturing. Unfortunately, some of the most useful technologies to advance genome editing in E. coli have not yet been ported into other bacterial species. For instance, the addition of bacterial retrons to the genome editing toolbox has increased the efficiency of recombineering in E. coli by enabling sustained, abundant production of ssDNA recombineering donors by reverse transcription that install flexible, precise edits in the prokaryotic chromosome. To extend the utility of this technology beyond E. coli, we surveyed the portability and versatility of retron-mediated recombineering across three different bacterial phyla (Proteobacteria, Bacillota and Actinomycetota) and a total of 15 different species. We found that retron recombineering is functional in all species tested, reaching editing efficiencies above 20% in six of them, above 40% in three of them, and above 90% in two of them. We also tested the extension of the recombitron architecture optimizations and strain backgrounds in a subset of hosts to additionally increase editing rates. The broad recombitron survey carried out in this study forms the basis for widespread use of retron-derived technologies through the whole Bacteria domain.

bioengineering↗

bioRxiv2024

In vitro metabolic interaction network of a rationally designed nasal microbiota community

Mounting evidence suggests that metabolite exchange between microbiota members is a key driver of microbiota composition. However, we still know little about the metabolic interaction networks that occur within many microbiota. This is particularly true for the nasal microbiota, and current efforts towards this end are hampered by a lack of microbial consortia that would enable the mapping of metabolic interactions between nasal microbiota members under in vitro conditions. To tackle these issues, we developed the Porcine Nasal Consortium (PNC8), a rationally designed microbial consortium of eight strains representing the most in vivo abundant genera in the nasal microbiota of healthy piglets. We used this consortium to systematically examine the metabolic capabilities of nasal microbiota members, as well as the metabolic interactions occurring between them. We found that PNC8 strains differ substantially in their metabolic pathway repertoire and ability to grow across various in vitro conditions. Nevertheless, spent-media experiments revealed that most metabolic interactions between PNC8 strains are negative, and exometabolomics data pointed to co-depletion of sugars as a key driver of this interaction network. Finally, direct co-cultivation experiments showed that, as a result of this largely negative metabolic interaction network, competition is common among pairs of PNC8 strains and leads to a complex competition hierarchy in which only few strains are able to consistently outcompete all others. Overall, this work provides a valuable resource for studying the nasal microbiota under experimentally tractable in vitro conditions and is a key step towards mapping its metabolic interaction network.

systems biology↗

bioRxiv2024

Porcine Nasal Organoids as a model to study the interactions between the swine nasal microbiota and the host

Interactions between the nasal epithelium, commensal nasal microbiota, and respiratory pathogens play a key role in respiratory infections. Currently there is a lack of experimental models to study such interactions under defined in vitro conditions. Here, we developed a Porcine Nasal Organoid (PNO) system from nasal tissue of pigs as well as from cytological brushes. PNOs exhibited similar structure and cell types than the nasal mucosa, as evaluated by immunostaining. PNOs were inoculated with porcine commensal strains of Moraxella pluranimalium, Rothia nasimurium and the pathobiont Glaesserella parasuis for examining host-commensal-pathogen interactions. All strains adhered to the PNOs, although at different levels. M. pluranimalium and G. parasuis strains stimulated the production of proinflammatory cytokines, whereas R. nasimurium induced the production of IFN{gamma} and diminished the proinflammatory effect of the other strains. Overall, PNOs mimic the in vivo nasal mucosa and can be useful to perform host-microbe interaction studies. In briefInteractions between nasal epithelium, commensal nasal microbiota, and respiratory pathogens play a key role in respiratory infections. We developed porcine nasal organoids to mimic the nasal mucosa and use as a model to study those interactions. Additionally, this development supports the reduction of the number of animals for animal experimentation. HighlightsO_LIFirst generation of Porcine Nasal Organoids (PNOs) from nasal turbinates and swabs C_LIO_LIPNOs recapitulate features of in vivo tissue and maintain self-renewal capacity C_LIO_LIHost-microbe interactions can be studied using the PNO system C_LIO_LIRothia nasimurium inhibits the inflammation induced by other bacteria C_LI

microbiology↗

bioRxiv2023

Gut-associated microbes are present and active in the pig nasal cavity

BackgroundThe nasal microbiota is a key contributor to animal health, and characterizing the nasal microbiota composition is an important step towards elucidating the role of its different members. Efforts to characterize the nasal microbiota composition of domestic pigs and other farm animals frequently report the presence of bacteria that are typically found in the gut, including many anaerobes from the Bacteroidales and Clostridiales orders. However, the in vivo role of these gut-microbiota associated taxa is currently unclear. Here, we tackled this issue by examining the prevalence, origin, and activity of these taxa in the nasal microbiota of piglets. ResultsFirst, analysis of the nasal microbiota of farm piglets sampled in this study, as well as various publicly available data sets, revealed that gut-microbiota associated taxa indeed constitute a substantial fraction of the pig nasal microbiota that is highly variable across individual animals. Second, comparison of herd-matched nasal and rectal samples at amplicon sequencing variant (ASV) level showed that these taxa are largely shared in the nasal and rectal microbiota, suggesting a common origin driven presumably by the transfer of fecal matter. Third, surgical sampling of the inner nasal tract showed that gut-microbiota associated taxa are found throughout the nasal cavity, indicating that these taxa do not stem from contaminations introduced during sampling with conventional nasal swabs. Finally, analysis of cDNA from the 16S rRNA gene in these nasal samples indicated that gut-microbiota associated taxa are indeed active in the pig nasal cavity. ConclusionThis study shows that gut-microbiota associated taxa are not only present, but also active, in the nasal cavity of domestic pigs, and paves the way for future efforts to elucidate the in vivo function of these taxa within the nasal microbiota.

microbiology↗

bioRxiv2023

The emergence and diversification of a zoonotic pathogen from within the microbiota of intensively farmed pigs

The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species this can affect the health of humans as well as livestock. Here we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of Streptococcus suis, a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of S. suis emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of S. suis and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of S. suis is yet to be fully realised.

evolutionary biology↗

bioRxiv2022

Streptococcus suis infection on European farms is associated with an altered tonsil microbiome and resistome

Streptococcus suis is a Gram-positive opportunistic pathogen causing systemic disease in piglets around weaning age. The factors predisposing to disease are not known. We hypothesised that the tonsillar microbiota might influence disease risk via colonisation resistance and/or co-infections. We conducted a cross-sectional case-control study within outbreak farms complemented by selective longitudinal sampling and comparison with control farms without disease occurrence. We found a small but significant difference in tonsil microbiota composition between case and control piglets (n=45+45). Variants of putative commensal taxa, including Rothia nasimurium, were reduced in abundance in case piglets compared to asymptomatic controls. Case piglets had higher relative abundances of Fusobacterium gastrosuis, Bacteroides heparinolyticus, and uncultured Prevotella and Alloprevotella species. Despite case-control pairs receiving equal antimicrobial treatment, case piglets had higher abundance of antimicrobial resistance genes (ARGs) conferring resistance to antimicrobial classes used to treat S. suis. This might be an adaption of disease-associated strains to frequent antimicrobial treatment.

microbiology↗