Biology subjects

Heilbronner, S.

Publications and source records attributed to Heilbronner, S..

18 recordsLinked to original sources

bioRxiv2026

Development of a continuous bioreactor to maintain stable nasal microbiomes from swab specimens and synthetic communities

BackgroundThe nasal microbiome is a collection of diverse microbial populations that inhabit the nose. Staphylococcus aureus is the most common opportunistic pathogen that colonizes the nasal mucosa, increasing the risk of invasive infections in immunocompromised and hospitalized patients. Clinicians usually prescribe antibiotics to decolonize the nasal cavities of at-risk patients from S. aureus. However, their broad antimicrobial activity can damage the resident nasal microbiome. Instead, naturally occurring compounds or resident bacteria in nasal microbiomes can effectively and safely exclude S. aureus from the nose. Cell culture and animal models have been used for nasal microbiome studies. However, their unstable microbiomes reduce the accuracy and reliability of the results. Recently, continuous bioreactors have been proposed as alternatives to these models. ResultsWe designed and operated a continuous bioreactor system to maintain stable nasal microbiomes. Next, we inoculated the bioreactor with nasal-swab specimens that we had collected from healthy volunteers. We operated the bioreactors under varying conditions (i.e., operating mode, dilution rate, temperature, pH, and medium composition), and determined the optimal conditions (continuous mode, 1 d-1, 30xlink:href=" pH 6.5, and synthetic nasal medium 3), resulting in stable microbiomes consisting of the main nasal bacterial species. The nasal microbiomes in the optimized bioreactors showed high reproducibility and resilience during a pH perturbation. Moreover, all microbiomes in the bioreactor, which were inoculated with six different nasal-swab specimens, maintained stable bacterial and metabolite compositions. In addition, we applied a synthetic microbial community (SynCom), which was derived from one of the volunteers, to demonstrate a S. aureus decolonization strategy. The bioreactor, inoculated with this SynCom, maintained a stable nasal microbiome for more than one month. Finally, different S. aureus strains that we inoculated in the SynCom showed distinct growth patterns within the otherwise stable community. ConclusionsThe continuous bioreactor enables the cultivation of stable nasal microbiomes for longer than one month by mimicking the environmental conditions of the human nose. The bioreactor is a valuable model for understanding the functions of the nasal microbiome and devising new decolonization strategies against S. aureus.

bioengineering↗

bioRxiv2026

A widespread SCCmec-located gene cluster protects methicillin-resistant Staphylococcus aureus against toxic polysulfides

The genus Staphylococcus contains important human commensals and pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which is a frequent colonizer of humans and a leading cause of healthcare-associated and life-threatening infections. While its virulence and pathogenicity have been extensively studied, factors driving the colonization and distribution of MRSA as a pathobiont are less understood. Here, we report on a cst sulfide detoxification gene cluster located on SCCmec, the antibiotic resistance-mediating genetic element of MRSA. Bioinformatic analyses revealed a heterogeneous distribution of cst clusters in staphylococcal genomes and that many clinically relevant SCCmec types introduce an additional cst cluster (cst2) to MRSA. While the canonical cst cluster (cst1) consists of the five genes tauE, cstR, cstA, cstB, and sqr, most staphylococcal cst clusters, including the SCCmec-located cst2, lack the sqr gene, which encodes for a sulfide:quinone reductase responsible for the initial step of sulfide detoxification. Growth experiments with a diverse set of representative Staphylococcus strains, cst-deletion mutants, and complementation with cst-containing plasmids demonstrated that the cst cluster enables sqr-independent polysulfide-detoxification. Furthermore, the additional cst2 cluster confers high polysulfide tolerance to MRSA, providing the pathogen with a unique advantage in polysulfide-rich environments. Using serial passaging co-cultivation experiments with methicillin-sensitive S. aureus (MSSA) strains, we demonstrated that in the presence of polysulfides cst2-containing MRSA can invade an established MSSA population and outperform the occupying resident in direct competition. Overall, our findings indicate that polysulfides are critical stress factors for staphylococci, potentially contributing to the spread of cst2-containing SCCmec and MRSA. ImportanceMethicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent human pathogens responsible for millions of life-threatening infections worldwide. It acquires antibiotic resistance through the genetic element SCCmec, which contains the characteristic mecA gene that renders the organism resistant to most classes of {beta}-lactam antibiotics. Besides mecA and accessory gene complexes necessary for the transfer of SCCmec and phenotype manifestation, the genetic element also contains prominent gene clusters with unknown functions. Here, we report on a (poly-)sulfide-detoxification gene cluster (cst2) present on SCCmec that provides MRSA with a unique advantage in environments containing polysulfides - highly reactive intermediates of sulfide oxidation naturally occurring as microbial stressors on mucosal surfaces inside the human body. We demonstrate that in the presence of polysulfides, cst2 enables MRSA to outperform non-MRSA in direct competition, thus supporting the invasion and proliferation of this pathogen independent of its antibiotic resistance.

microbiology↗

bioRxiv2026

Community composition and strain identity drive metabolic competition and Staphylococcus aureus colonization resistance in Synthetic Nasal Communities

The human nasal microbiome is a low-diversity ecosystem whose assembly principles and mechanisms of colonization resistance remain poorly understood. Staphylococcus aureus is a member of the nasal microbiome of some individuals with variable abundance. We hypothesized that nutritional competition, strain-level diversity, and nutrient availability shape community stability and the ability of commensal species to inhibit S. aureus. To test this, we constructed 50 defined synthetic communities composed of representative human nasal bacteria differing in strain and species composition and tracked their temporal dynamics, S. aureus growth, metabolic profiles, and nutritional interactions. The composition of synthetic communities with 5-10 species showed robust and reproducible dynamics and converged in one of three stable states. Synthetic communities dominated by a specific strain of Corynebacterium propinquum were highly stable and consistently excluded S. aureus. Growth curves and coculture assays showed that C. propinquum outcompetes S. aureus under poor nutritional conditions resembling the nasal environment, whereas S. aureus dominates in nutrient-rich conditions. Metabolomics analyses revealed that nutritional competition, including siderophores utilization and amino acid limitation, likely underlies this colonization resistance. These results establish a tractable synthetic community model for the human nasal microbiome and identify nutrient-dependent competition and microbial metabolite production as key drivers of community structure and pathogen exclusion.

microbiology↗

bioRxiv2025

Diffusion-weighted steady-state free precession imaging in the ex vivo macaque brain on a 10.5T human MRI scanner

Diffusion MRI provides a non-invasive probe of local fibre bundles and long-range anatomical connections to characterise the structural connectome. One way to achieve very high spatial resolution diffusion MRI data for connectivity investigations is to scan ex-vivo brains over many hours or days, ideally at ultra-high field strength to boost signal levels. However, conventional diffusion MRI acquisition techniques do not generally deliver good data quality for the challenging conditions of ex-vivo tissue, characterised by reduced diffusivities and relaxation times when compared to in vivo. In this work, we investigate the potential of the diffusion-weighted steady-state free precession (DW-SSFP) sequence for ex vivo diffusion imaging of the macaque brain using a 10.5 T human MRI scanner with a conventional (Gmax = 70 mT/m) gradient set. SNR-efficiency optimisations incorporating experimental relaxation times demonstrate that the DW-SSFP sequence is predicted to achieve improved or similar SNR efficiency compared to a diffusion-weighted spin- and stimulated-echo sequence. Importantly, DW-SSFP can achieve this with the additional benefit of negligible geometric distortions, unlike conventional diffusion MRI using an echo-planar imaging readout. Using optimised DW-SSFP sequence parameters, we propose a protocol at 0.4 mm isotropic resolution using a two-shell multi-orientation protocol (effective b-values of 3200 s/mm2 and 5600 s/mm2). We fit the data using Tensor, Ball and 3-Sticks and Constrained Spherical Deconvolution signal representations. The results demonstrate high-quality diffusivity estimates across the entire brain with the ability to resolve multiple fibre populations in challenging crossing-fibre regions. The data will be made fully open source and multimodal as part of the Center for Mesoscale Connectomics, providing a resource for future connectivity investigations.

neuroscience↗

bioRxiv2025

NMDA receptor ablation in medial prefrontal cortex disrupts value updating and reward history integration

Schizophrenia, a serious mental illness, is associated with evidence of NMDA receptor (NMDAR) dysfunction and characterized by cognitive impairments that reflect impaired value updating and feedback-driven control; however the cellular and circuit-level mechanisms underlying these disruptions remain unclear. Here we test how NMDA receptor (NMDAR) signaling in the medial prefrontal cortex (mPFC) contributes to adaptive decision-making by combining targeted genetic ablation in mice and systemic pharmacology. Using a CRISPR-Cas9 approach to eliminate the obligate GluN1 subunit, we induced spatially confined NMDAR hypofunction in mPFC and compared its effects to systemic pharmacological blockade with the NMDAR antagonist MK-801 during performance of a touchscreen-based restless bandit task. Prefrontal NMDAR ablation impaired value discrimination, weakened the use of negative feedback, and reduced mutual information between recent outcomes and current choices, indicating disrupted reward-history integration. Reinforcement-learning models incorporating a choice-kernel term best captured behavior and revealed that NMDAR ablation selectively dampened learning and choice-history parameters governing flexible updating. Systemic MK-801 produced broad impairments in control animals, reducing accuracy, mutual information, and outcome sensitivity, yet exerted only modest additional effects after NMDAR ablation, suggesting that prefrontal NMDAR loss occluded much of the pharmacological disruption. Simulations using fitted RLCK parameters reproduced these patterns, showing convergent flattening of choice dynamics under MK-801 and persistent deficits in GluN1 ablated animals. Together, these findings demonstrate that prefrontal NMDAR signaling is necessary for effective value updating and feedback-driven learning, and that its loss recapitulates core features of systemic NMDAR hypofunction. This work establishes a mechanistic bridge between localized cortical glutamatergic dysfunction and the reinforcement-learning disturbances characteristic of schizophrenia.

neuroscience↗

bioRxiv2025

A semantotopic map in human hippocampus

The hippocampus plays a central role in encoding abstract conceptual and semantic information. However, little is known about the topography of that encoding. We leveraged the rare opportunity to examine neural responses densely along a small portion of the human hippocampus, specifically, the mediolateral axis of the anterior body. We collected responses to passive language listening using Neuropixels probes in three anesthetized patients during clinically indicated neurosurgical procedures. We computed semantic tuning functions for each recording site by regressing threshold crossing events and single unit responses against semantic embeddings from GPT-2, Word2Vec, and SBERT. We find that tuning functions of more distant recording sites are more dissimilar, supporting the hypothesis semantotopic organization. Multiple semantic features showed systematic changes along that axis, including animacy, concreteness, and familiarity; notably, effects were individual-specific. Surprisingly, we also found a small but significant increase in semantic similarity as a function of distance between recording sites, on a shorter spatial scale, suggesting a modest periodic organization. Together, these results demonstrate the presence of a multiscale functional organization of semantics in the hippocampus.

neuroscience↗

bioRxiv2025

A single transcriptional regulator is crucial for the adaptation of Staphylococcus aureus to diverse niches

The adaptation of versatile multi-host pathogens to various hosts and various niches within hosts is often still poorly understood. The alternative Sigma factor B (SigB) is the master regulator of the general stress response of most gram-positive bacteria, which is a classic case of adaptive plasticity. In Staphylococcus aureus, SigB appears co-opted to function as a switch between intracellular and extracellular niches. During bovine mastitis, low SigB-activity confers an advantage in the milk-rich extracellular niche of the bovine udder. We show that narrowly adapted SigB-deficient strains evolved repeatedly from phenotypically plastic SigB-wildtype strains during persistent mastitis. This genetic assimilation appears driven by the cost of phenotypic plasticity: long time lags in adapting to milk and slow growth. Surprisingly, we observe that mutations causing SigB-deficiency allow even human isolates to grow in milk. While host adaptation often proceeds by mobile genetic elements exchanged between strains, we show how a master regulator in the core genome can drive niche adaptation.

microbiology↗

bioRxiv2025

Tyrosine availability shapes Staphylococcus aureus nasal colonization and interactions with commensal communities

Only certain individuals are nasally colonized by Staphylococcus aureus, making them more susceptible to developing endogenous infections. The role of the resident microbiota in modulating S. aureus nasal colonization remains largely unclear. Using a newly assembled nasal strain collection, we demonstrate that nasal commensals can either promote or inhibit S. aureus proliferation through strain- and community-specific effects in vitro and within gnotobiotic animals. We identified nutrient-dependent interactions as a key driver of these dynamics and found that S. aureus strains auxotrophic to tyrosine rely on amino acid-providing nasal communities to thrive in the nutrient-limited environment of the nose. Large-scale screenings revealed tyrosine dependency to affect 8% of nasal S. aureus strains and to impair S. aureus colonization. Our findings uncover a crucial factor in S. aureus physiology and its interactions as a commensal nasal species, paving the way for new decolonization strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/651429v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@17b6289org.highwire.dtl.DTLVardef@182249forg.highwire.dtl.DTLVardef@1324dc1org.highwire.dtl.DTLVardef@18ec3bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Cross-species Standardised Cortico-Subcortical Tractography

Despite their importance for brain function, cortico-subcortical white matter tracts are underrepresented in diffusion MRI tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed protocols are robust against data quality and preserve aspects of individual variability stemming from family structure in humans. Lastly, we demonstrate the value of these species-matched protocols in mapping homologous grey matter regions in humans and macaques, both in cortex and subcortex.

neuroscience↗

bioRxiv2025

Parietal cortex is recruited by frontal and cingulate areas to support action monitoring and updating during stopping

Recent evidence indicates that the intraparietal sulcus (IPS) may play a causal role in action stopping, potentially representing a novel neuromodulation target for inhibitory control dysfunctions. Here, we leverage intracranial recordings in human subjects to establish the timing and directionality of information flow between IPS and prefrontal and cingulate regions during action stopping. Prior to successful inhibition, information flows primarily from the inferior frontal gyrus (IFG), a critical inhibitory control node, to IPS. In contrast, during stopping errors the communication between IPS and IFG is lacking, and IPS is engaged by posterior cingulate cortex, an area outside of the classical inhibition network and typically associated with default mode. Anterior cingulate and orbitofrontal cortex also display performance-dependent connectivity with IPS. Our functional connectivity results provide direct electrophysiological evidence that IPS is recruited by frontal and anterior cingulate areas to support action plan monitoring/updating, and by posterior cingulate during control failures. In briefFunctional connectivity between the intraparietal sulcus (IPS) and a set of frontal and cingulate regions indicates that IPS is recruited to aid inhibitory control. Control failures are associated with increased communication with posterior cingulate. IPS could be a novel and tractable neuromodulation target for control-related neuropsychiatric disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/640787v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@e04699org.highwire.dtl.DTLVardef@3b1ea6org.highwire.dtl.DTLVardef@15961f4org.highwire.dtl.DTLVardef@12e144f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIParietal cortex displays performance-dependent activity in action stopping C_LIO_LIFunctional connectivity between IPS and IFG underlies successful stopping C_LIO_LIEarly communication from ACC and OFC to IPS is also specific to successful stopping C_LIO_LICommunication from PCC to IPS is higher during lapses in control C_LI

neuroscience↗

bioRxiv2024

Siderophore piracy enables the nasal commensal Staphylococcus lugdunensis to antagonize the pathogen Staphylococcus aureus

Bacterial pathogens such as Staphylococcus aureus colonize body surfaces of part of the human population, which represents a critical risk factor for skin disorders and invasive infections. However, such pathogens do not belong to the human core microbiomes - beneficial commensal bacteria can often prevent the persistence of certain pathogens - using molecular strategies that are only superficially understood. We recently reported that the commensal bacterium Staphylococcus lugdunensis produces the novel antibiotic lugdunin, which eradicates S. aureus from nasal microbiomes of hospitalized patients. However, it has remained unclear if S. lugdunensis may affect S. aureus carriage in the general population and how S. lugdunensis carriage could be promoted to enhance its S. aureus-eliminating capacity. We could cultivate S. lugdunensis from the noses of 6.3% of healthy human volunteers. In addition, S. lugdunensis DNA could be identified in metagenomes of many culture-negative nasal samples indicating that cultivation success depends on a specific bacterial threshold density. Healthy S. lugdunensis carriers had a 5.2-fold lower propensity to be colonized by S. aureus indicating that lugdunin can eliminate S. aureus also in healthy humans. S. lugdunensis-positive microbiomes were dominated by either Staphylococcus epidermidis, Corynebacterium species, or Dolosigranulum pigrum. These and further bacterial commensals, whose abundance was positively associated with S. lugdunensis, promoted S. lugdunensis growth in co-culture. Such mutualistic interactions depended on the production of iron-scavenging siderophores by supporting commensals, and on the capacity of S. lugdunensis to import siderophores. These findings underscore the importance of microbiome homeostasis for eliminating pathogen colonization. Elucidating mechanisms that drive microbiome interactions will become crucial for microbiome-precision editing approaches.

microbiology↗

bioRxiv2024

Nasal commensals reduce Staphylococcus aureus proliferation by restricting siderophore availability

BackgroundThe human microbiome is critically associated with human health and disease. One aspect of this is that antibiotic-resistant opportunistic bacterial pathogens such as methicillin-resistant Staphylococcus aureus can reside within the nasal microbiota which increases the risk of infections. Epidemiological studies of the nasal microbiome have revealed positive and negative correlations between non-pathogenic species and S. aureus, but the underlying molecular mechanisms remain poorly understood. The nasal cavity is iron-limited and bacteria are known to produce iron-scavenging siderophores to proliferate in such environments. Siderophores are public goods that can be consumed by all members of a bacterial community. Accordingly, siderophores are known to mediate bacterial competition and collaboration but their role in the nasal microbiome is unknown. ResultsHere we show that siderophore acquisition is crucial for S. aureus nasal colonization in vivo. We screened 94 nasal bacterial strains from seven genera for their capacity to produce siderophores as well as to consume the siderophores produced by S. aureus. We found that 80% of the strains engaged in siderophoremediated interactions with S. aureus. Non-pathogenic corynebacterial species were found to be prominent consumers of S. aureus siderophores. In co-culture experiments, consumption of siderophores by competitors reduced S. aureus growth in an iron-dependent fashion. ConclusionsOur data show a wide network of siderophore mediated interactions between the species of the human nasal microbiome and provide mechanistic evidence for inter-species competition and collaboration impacting pathogen proliferation. This opens avenues for designing nasal probiotics to displace S. aureus from the nasal cavity of humans.

microbiology↗

bioRxiv2023

An interbacterial lipase toxin with an unprecedented reverse domain arrangement defines a new class of type VII secretion system effector

The type VII protein secretion system (T7SS) is found in many Gram-positive bacteria and in pathogenic mycobacteria. All T7SS substrate proteins described to date share a common helical domain architecture at the N-terminus that typically interacts with other helical partner proteins, forming a composite signal sequence for targeting to the T7SS. The C-terminal domains are functionally diverse and in Gram-positive bacteria such as Staphylococcus aureus often specify toxic anti-bacterial activity. Here we describe the first example of a new class of T7 substrate, TslA, that has an unexpected reverse domain organisation. TslA is widely found across Bacillota including Staphylococcus, Enterococcus and Listeria. We show that the S. aureus TslA N-terminal domain is a phospholipase A with anti-staphylococcal activity that is neutralised by the immunity lipoprotein TilA. Two small helical partner proteins, TlaA1 and TlaA2 are essential for T7-dependent secretion of TslA and at least one of these interacts with the TslA C-terminal domain to form a helical stack. Cryo-EM analysis of purified TslA complexes indicate that they share structural similarity with canonical T7 substrates. Our findings suggest that the T7SS has the extraordinary feature of recognising a secretion signal present at either end of a substrate.

microbiology↗

bioRxiv2023

Genome-scale metabolic models consistently predict in vitro characteristics of Corynebacterium striatum

Genome-scale metabolic models (GEMs) are organism specific knowledge bases which can be used to unravel pathogenicity or improve production of specific metabolites in biotechnology applications. The present work combines in silico and in vitro approaches to create and curate strain-specific genome-scale metabolic models of Corynebacterium striatum. Approaches towards modeling rarely studied organisms are scarce. We introduce a cost-effective and easy experimental protocol which can be adapted to other organisms as well. Furthermore, the comparability of growth kinetics and in silico growth rates is discussed. This work introduces five newly created strain-specific genome-scale metabolic models (GEMs) of high quality, satisfying all contemporary standards and requirements. All these models have been benchmarked using the community standard test suite Metabolic Model Testing (MEMOTE) and experimentally validated by laboratory experiments conducted specifically for this purpose. For the curation of those models, the software infrastructure refineGEMs was developed to work on these models in parallel and to comply with the quality standards for GEMs. The model predictions were confirmed by experimental data and a new comparison metric based on the doubling time was developed to quantify bacterial growth. Future modeling projects can rely on the proposed software, which is independent of specific environmental conditions. The validation approach based on the growth rate calculation is now accessible and closely aligned with biological questions. The curated models are freely available via BioModels and a GitHub repository and can be used. The open-source software refineGEMs is available from https://github.com/draeger-lab/refinegems.

systems biology↗

bioRxiv2023

Functional membrane microdomains and the hydroxamate siderophore transporter ATPase FhuC govern Isd-dependent heme acquisition in Staphylococcus aureus

Sufficient access to transition metals such as iron is essential for bacterial proliferation and their active limitation within host tissues effectively restricts infection. To overcome iron limitation, the invasive pathogen Staphylococcus aureus uses the iron-regulated surface determinant (Isd) system to acquire hemoglobin-derived heme. While heme transport over the cell wall is well understood, its transport over the membrane is hardly investigated. In this study, we show the heme-specific permease IsdF to be energized by the general ATPase FhuC. Additionally, we show that IsdF needs appropriate location within the membrane for functionality. The membrane of S. aureus possesses special compartments (functional membrane microdomains - FMMs) to organize membrane complexes. We show IsdF to be associated with FMMs, to directly interact with the FMM scaffolding protein flotillin A (FloA) and to co-localize with the latter on intact bacterial cells. Additionally, Isd-dependent bacterial growth required FMMs and FloA. Our study shows that Isd-dependent heme acquisition requires a highly structured cell envelope to allow coordinated transport over the cell wall and membrane and it gives the first example of a bacterial nutrient acquisition system that depends on FMMs.

microbiology↗

bioRxiv2022

Horizontal transfer of bacteriocin biosynthesis genes requires metabolic adaptation to improve compound production and cellular fitness

Biosynthetic gene clusters (BGCs) encoding the production of bacteriocins are widespread amongst bacterial isolates and are important genetic determinants of competitive fitness within a given habitat. Staphylococci produce a tremendous diversity of compounds and the corresponding BGCs are frequently associated with mobile genetic elements, suggesting gain and loss of biosynthetic capacity. Pharmaceutical biology has shown that compound production in heterologous hosts is often challenging and many BGC recipients produce initially low compound amounts or show reduced growth rates. To assess whether transfer of BGCs between closely related S. aureus strains can be instantly effective or requires elaborate metabolic adaptation, we investigated the intra species transfer of a BGC encoding the ribosomally synthesized and post-translationally modified peptide (RiPP) micrococcin P1 (MP1). We found that acquisition of the BGC by S. aureus RN4220 enabled immediate MP1 production but also imposed a metabolic burden, which was relieved after prolonged cultivation by adaptive mutation. We used a multiomics approach to study this phenomenon and found adaptive evolution to select for strains with increased activity of the tricarboxylic acid cycle (TCA), which enhanced metabolic fitness and levels of compound production. Metabolome analysis revealed increases of central metabolites including citrate and -ketoglutarate in the adapted strain, suggesting metabolic adaptation to overcome the BGC-associated growth defects. Our results indicate that BCG acquisition requires genetic and metabolic predispositions allowing the integration of bacteriocin production into the cellular metabolism. Inappropriate metabolic characteristics of recipients can entail physiological burdens, negatively impacting the competitive fitness of recipients within natural bacterial communities. ImportanceHuman microbiomes are critically associated with human health and disease. Importantly, pathogenic bacteria can hide in human associated communities and can cause disease when the composition of the community becomes dysbalanced. Bacteriocin producing commensals are able to displace pathogens from microbial communities, suggesting that their targeted introduction in human microbiomes might prevent pathogen colonisation and infection. However, in view of future probiotic approaches, strains are needed that produce high levels of bioactive compounds and retain cellular fitness within mixed bacterial communities. Our work offers insights into the metabolic burdens associated with the production of the bacteriocin micrococcin P1 and highlights evolutionary strategies that increase cellular fitness in the context of production. Most likely metabolic adaptations are broadly relevant for bacteriocin producers and need to be considered for the future development of effective microbiome editing strategies.

microbiology↗

bioRxiv2022

In vivo growth of Staphylococcus lugdunensis is facilitated by the concerted function of heme and non-heme iron acquisition mechanisms

Acquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Here we show that S. lugdunensis utilizes diverse genome encoded iron acquisition mechanisms to satisfy its need for this nutrient. Indeed, S. lugdunensis can usurp hydroxamate siderophores, and staphyloferrin A and B from S. aureus, using the fhuC ATPase-encoding gene. Acquisition of catechol siderophores and catecholamine stress hormones necessitates the presence of the sst-1 transporter-encoding locus, but not the sst-2 locus. Iron-dependent growth in acidic culture conditions necessitates the feoAB locus. Heme iron is acquired via expression of the iron-regulated surface determinant (isd) locus. During systemic infection of mice we demonstrate that while S. lugdunensis does not cause overt illness, it does colonize and proliferate to high numbers in the kidneys. By combining mutations in the various iron acquisition loci, we further demonstrate that only a strain mutated for all of isd, fhuC, sst-1, and feo, versus combination mutants carrying wild type copies of any one of those loci, was attenuated in its ability to proliferate to high numbers in kidneys. Taken together our data reveal that S. lugdunensis requires a repertoire of both heme and non-heme iron acquisition mechanisms to proliferate during systemic infection of mammals. ImportanceAcquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Owing to an inability to synthesize siderophores, growth of S. lugdunensis is dramatically impaired in the presence of transferrin or serum, yet S. lugdunensis nonetheless uses several other genome-encoded iron acquisition mechanisms, in concert, to proliferate within the mammalian host. Therefore, the development of interventions that target bacterial iron acquisition systems should consider the overlapping function of distinct metal acquisition strategies deployed by bacterial pathogens.

microbiology↗

bioRxiv2020

Anatomically distinct OFC-PCC circuits relay choice from value space to action space

Economic choice necessarily involves the transformation of abstract, object-based representations to concrete, action-based ones. This transformation is both determined and delimited by the neuroanatomical organization of the regions that implement it. In choice, the orbitofrontal cortex (OFC) plays a key role in both abstract valuation and cognitive mapping. However, determining the neural processes underlying this transformation has proven difficult. We hypothesized that difficulty stems from in part from the fact that the OFC consists of multiple functionally distinct zones that are distinguished by their differing contributions to the abstract-concrete transformation, and that these functions reflect their differing long-range projections. Here we identify two such subregions, defined by stronger or weaker bidirectional anatomical connectivity with the posterior cingulate cortex (PCC). We call these regions OFCin and OFCout, respectively. We find that OFCin, relative to OFCout, shows enhanced functional connectivity with PCC, as indicated by both spike-field coherence and mutual information. We find converging evidence that the OFCin-PCC circuit, but not the OFCout-PCC circuit, relays choice signals from an abstract value space to a concrete action space. Moreover, the OFCin-PCC circuit shows a putative bidirectional mutually excitatory pattern. Together, these results support the hypothesis that OFC-PCC subareal organization is critical for understanding the implementation of offer-action transformation in economic choice.

neuroscience↗