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Optimization of prophylactic vaccine regimens to elicit strong, long-lasting immunity is an urgent need highlighted by the COVID-19 pandemic. Stronger vaccine immunogenicity is frequently reported in individuals living in high-income countries compared to individuals living in low- and middle-income countries. While numerous host genetic and immune factors may influence vaccine responses, geographic restrictions to vaccine effectiveness may also be influenced by the intestinal microbiota, which modulates host immune systems. However, the potential role of the gut microbiota on responses to HIV-1 vaccines has not yet been explored. We analyzed the bacteriome by targeted 16S sequencing and the virome by virus-like particle sequencing of 154 fecal samples collected from healthy individuals in Uganda, Rwanda, and the United States early (week 2) and late (week 26) after vaccination with multivalent adenovirus serotype 26 (Ad26)-vectored mosaic HIV-1 vaccines. Vaccination did not affect the enteric bacteriome or virome regardless of geographic location. However, geography was the major driver of microbiota differences within this cohort. Differences in overall bacterial and viral diversity and in specific microbial taxa, including Bacteroidota and Bacillota, between participants from the United States and East African countries correlated with differential immune responses, including specific antibody titers, antibody functionality, and cellular immune responses to vaccination regimens. These findings support the microbiota as a putative modifier of vaccine immunogenicity.IMPORTANCEOur research examined how gut bacteria might influence vaccine effectiveness in different parts of the world. We studied adults from the United States, Rwanda, and Uganda who received an experimental HIV vaccine. We found that participants from East Africa had more diverse gut bacteria than those from the United States, but their immune responses to the vaccine were weaker. This is the first study to directly show this relationship between higher gut bacterial diversity and reduced vaccine effectiveness in the same group of people. We also identified specific types of bacteria that were linked to either stronger or weaker immune responses. These findings are particularly relevant now as we use vaccines globally to fight diseases like COVID-19, as they suggest that regional differences in gut bacteria Bacteroidota and Bacillota might help explain why vaccines work better in some places than others. This could inform how we design and test future vaccines.

Microbial interactions in cheese rinds influence community structure, food safety, and product quality. But the chemical mechanisms that mediate microbial interactions in cheeses and other fermented foods are generally not known. Here, we investigate how the spoilage mold Aspergillus westerdijkiae chemically inhibits beneficial cheese-rind bacteria using a combination of omics technologies. In cheese-rind community and co-culture experiments, A. westerdijkiae strongly inhibited most cheese-rind community members. In co-culture with Staphylococcus equorum, A. westerdijkiae strongly affected bacterial gene expression, including upregulation of a putative bceAB gene cluster that is associated with resistance to antimicrobial compounds in other bacteria. Mass spectrometry imaging revealed spatially localized production of secondary metabolites, including penicillic acid and ochratoxin B at the fungal-bacterial interface with Brachybacterium alimentarium. Integration of liquid chromatography-tandem mass spectrometry and genome annotations confirmed the presence of additional bioactive metabolites, such as notoamides and circumdatins. Fungal metabolic responses varied by bacterial partner, suggesting species-specific chemical strategies. Notably, penicillic acid levels increased 2.5-fold during interaction with B. alimentarium, and experiments with purified penicillic acid showed inhibition in a dose-dependent manner against this rind bacterium. These findings show that A. westerdijkiae deploys a context-dependent suite of mycotoxins and other metabolites, disrupting microbial community assembly in cheese rinds.IMPORTANCEThis study identifies the chemical mechanisms underlying the negative impacts of Aspergillus westerdijkiae on cheese-rind development, revealing how specialized metabolites like penicillic acid and ochratoxin B influence rind bacterial communities. By integrating biosynthetic gene cluster analyses with mass spectrometry, we demonstrate how chemical communication shapes microbial interactions, with possible implications for food safety and cheese quality. Understanding these interactions is essential for assessing the risks of fungal-driven spoilage and mycotoxin production in cheese-rind maturation. Beyond cheese, these findings contribute to broader microbiome ecology, emphasizing how secondary metabolites mediate microbial competition in natural and fermented food environments.

This study aims to characterize the phenotypic behavior and in vivo persistence of a ceftriaxone-tolerant Neisseria gonorrhoeae clinical isolate from a single patient and evaluate the potential role of tolerance in treatment failure. A previously identified ceftriaxone-tolerant vaginal isolate was compared with isogenic and clinical non-tolerant strains. Bacterial growth was assessed in vitro, and tolerance was quantified using the minimum duration required to kill 99% of the population (MDK99), and persistence was evaluated in an in vivo Galleria mellonella infection model. Whole-genome sequencing (WGS) and transcriptomic (RNA-sequencing [RNA-seq]) profiling were performed to identify tolerance-associated genetic and transcriptional signatures. The tolerant strain exhibited prolonged MDK99 values across ceftriaxone concentrations, persisting for up to 24 hours under drug exposure. It also showed delayed early-phase growth, suggesting a fitness cost. In vivo, the tolerant strain remained viable up to 8 hours after treatment, whereas non-tolerant strains were cleared. WGS revealed identical gene content across all isolates, but non-synonymous mutations in pilE_3, a type IV pilin gene, were exclusively present in tolerant strains. RNA-seq analysis showed upregulation of pilin-associated genes and downregulation of zinc-independent ribosomal paralogs (rpmE2 and ykgO), suggesting a combined mechanism of surface remodeling and translational suppression associated with the tolerant phenotype. Ceftriaxone tolerance enables prolonged survival of N. gonorrhoeae despite apparent susceptibility by standard MIC-based testing. This phenotype may contribute to treatment failure, recurrent infection, and ongoing transmission, indicating the need for revised diagnostic and therapeutic strategies.IMPORTANCECeftriaxone remains the last reliable option for gonorrhea therapy, yet recurrent infections can occur despite isolates being classified as susceptible by MIC testing. One possible explanation is antibiotic tolerance, a phenotype that allows survival during drug exposure without changes in MIC. Although tolerance has been described in other pathogens, its role in gonococcal infection has remained poorly defined. In this study, we provide the first detailed characterization of a ceftriaxone-tolerant Neisseria gonorrhoeae clinical isolate associated with repeated treatment failure. By combining in vitro killing assays, an in vivo Galleria mellonella infection model, whole-genome sequencing, and transcriptomic profiling, we demonstrate that tolerance enables prolonged survival under ceftriaxone and is linked to pilin gene variation and ribosomal remodeling. These findings illustrate how a clinically observed phenomenon can be mechanistically dissected and emphasize tolerance as a hidden factor contributing to gonococcal persistence and potential treatment failure.

Bacteria produce a diverse range of specialized metabolites that influence the health and behavior of neighboring cells and, therefore, have potential applications in treating diseases. Deciphering the intended ecological functions of specialized metabolites is challenging due to the small scales at which these interactions occur and the complexity of unraveling simultaneous responses to multiple signals. In this study, we investigated the chemical interactions between two marine bacterial colonies, Vibrio parahaemolyticus PSU5429 and Bacillus pumilus YP001. When the two bacteria were grown in proximity on agar, V. parahaemolyticus exhibited swarming motility toward B. pumilus, but close approach to the B. pumilus colony was impeded by a zone of inhibition. Matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF IMS) suggested that lipopeptides produced by Bacillus induced swarming motility, a finding corroborated by genomic and chemical analyses of YP001. Based on activity and metabolomics guidance, the antibiotic amicoumacin B was found to be responsible for the observed antibiosis, while swarming motility by V. parahaemolyticus was induced by lipopeptides and two lipoamides. In this scenario, lipopeptide production by the Bacillus colony induces the Vibrio colony to swarm toward a lysis zone, resulting in a possible "catch and kill" effect. These results demonstrate the complexity of behaviors and outcomes exhibited by microbes under the simultaneous influence of different allelochemicals, suggesting possible interplays between antibiotics and compounds that induce motility.

Importance: Microbes communicate and compete using small molecules, yet linking specific metabolites to visible behaviors is difficult. We combine imaging mass spectrometry, genomics, analytical chemistry, and bioassays to decode an interaction between a marine Bacillus and the pathogen Vibrio parahaemolyticus. Surfactin-like lipopeptides act at a distance to stimulate Vibrio swarming and draw cells toward the colony. Amicoumacin B accumulates at the interface and halts growth, yielding a simple "catch and kill" outcome. This study shows that the spatial localization of natural products shapes microbial behavior on surfaces and provides a general, scalable workflow that maps chemistry to phenotype. Beyond this case, the approach can be applied broadly to understand and, ultimately, tune microbial interactions relevant to marine ecosystems, aquaculture health, and microbiome engineering.

The National Institute of Allergy and Infectious Diseases (NIAID) Data Ecosystem Discovery Portal (https://data.niaid.nih.gov) provides a unified search interface for over 4 million data sets relevant to infectious and immune-mediated disease (IID) research. Integrating metadata from domain-specific and generalist repositories, the Portal enables researchers to identify and access data sets using user-friendly filters or advanced queries, without requiring technical expertise. The Portal supports discovery of a wide range of resources, including epidemiological, clinical, and multi-omic data sets and is designed to accommodate exploratory browsing and precise searches. The Portal provides filters, prebuilt queries, and data set collections to simplify the discovery process for users. The Portal additionally provides documentation and an API for programmatic access to harmonized metadata. By easing access barriers to important biomedical data sets, the NIAID Data Ecosystem Discovery Portal serves as an entry point for researchers working to understand, diagnose, or treat IID.IMPORTANCEValuable data sets are often overlooked because they are difficult to locate. The NIAID Data Ecosystem Discovery Portal fills this gap by providing a centralized, searchable interface that empowers users with varying levels of technical expertise to find and reuse data. By standardizing key metadata fields and harmonizing heterogeneous formats, the Portal improves data findability, accessibility, and reusability. This resource supports hypothesis generation, comparative analysis, and secondary use of public data by the IID research community, including those funded by NIAID. The Portal supports data sharing by standardizing metadata and linking to source repositories and maximizes the impact of public investment in research data by supporting scientific advancement via secondary use.

Staphylococcus aureus clonal complex 59 (CC59) has emerged as a significant public health threat in Asia, yet the mechanisms driving its host adaptation and global evolutionary success remain poorly understood. Here, we performed a comprehensive genomic analysis of 3,994 global CC59 isolates, which included 549 isolates associated with bloodstream infections from China. Our analysis revealed three phylogenetically distinct lineages exhibiting region-specific distribution patterns, tracing their origins to the USA, Australia, and China. Notably, high-risk CC59 clones circulating in Taiwan likely diverged from mainland Chinese strains during the 1940s-1960s, coinciding with historical population migration following the Chinese civil war around 1949. Among China-associated CC59 strains, respiratory tract colonization was related to high cross-source linkage across multiple ecological niches, suggesting its role as a dissemination hub, particularly for bloodstream infection (BSI). Additionally, we observed significant enrichment of Clf-Sdr family proteins in human isolates, especially in BSI cases. Functional characterization using ΔclfB and ΔsdrD knockout strains demonstrated impaired biofilm formation, recapitulating findings in USA300. These findings establish an evolutionary framework for CC59 surveillance and highlight promising potential targets for anti-virulence therapeutics.

Importance: The prevalence and propagation of Staphylococcus aureus clonal complex 59 (CC59) in Asia are serious public health concerns. To understand its adaptation to hosts and worldwide evolutionary success, we analyzed the genomic population structure of all CC59 isolates and traced their evolutionary history. Our research indicates that CC59 lineages developed through unique evolutionary routes that vary across time and space, highlighting their adaptation to diverse ecological environments. This study presents a comprehensive genomic epidemiology framework that integrates extensive metadata analysis with evolutionary assessment. It serves as a model for future S. aureus monitoring and provides insights into potential targets for interventions focused on reducing virulence.

Hundreds of thousands of individual microbe-molecule interactions regulate the flux, transformation, and fate of carbon stored in the climatically important reservoir of marine dissolved organic matter (DOM). While marine microbial communities have been characterized at high resolution for over a decade, observations of the molecules cycled by the microbial-chemical network at similar resolution are limited. In addition, bulk characterizations of DOM can mask the complex network of interactions comprised of rich chemical diversities. Here, we present a three-year, depth-resolved, molecular time-series of DOM and prokaryoplankton at the Bermuda Atlantic Time-series Study (BATS) site. Both time-series exhibited seasonality that was compositionally distinct and primarily endemic to one sampling depth. We also putatively identified four exometabolites (gonyol, glucose-6-sulfate, succinate, and trehalose) that exhibit seasonal accumulation. We hypothesize these patterns result from environmental conditions that alter community composition on a seasonal timescale and thus shift the relative proportions of microbial functions that produce and consume the substrates. Critically, we observed the interannual composition of seasonal DOM molecules to be more stable than the taxonomy of the microbial community. This points to an important role of functional redundancy in regulating DOM composition. We tested this observation by querying metagenomes for pathways that utilize metabolic by-products putatively identified in the DOM time-series. We find that core microbial metabolisms, either those required by all or by a subset of marine microbes, are important predictors of DOM composition. The molecular-level characterization of DOM herein highlights the potential imprint of microbial activity on seasonal DOM composition.IMPORTANCEMarine dissolved organic matter (DOM) is a major carbon reservoir that acts as a critical control on the Earth's climate. DOM dynamics are largely regulated by a complex web of chemical-microbial interactions, but the mechanisms underpinning these processes are not well understood. In a three-year time-series, we found that the identity of the microbes is more likely to change between years than the composition of the DOM molecules. The taxonomic variability suggests that metabolisms shared across taxa, encoded by genes that conduct core microbial functions, are responsible for the more stable composition of DOM. While more than three decades of marine prokaryoplankton time-series are available, a similar reference for DOM molecules was missing. This time-series provides an improved understanding of the different responses of DOM molecules and microbes to seasonal environmental changes.

In this study, we used single-cell sequencing to analyze the gut microbiome of an adult male patient with acute cerebral hemorrhage undergoing antibiotic treatment. We identified 92 bacterial species, including 23 Firmicutes and one archaeon from Methanobacteriota, along with 69 unclassified strains. Single-cell sequencing effectively detected bacteria carrying antibiotic resistance genes (ARGs), particularly in unclassified species, and traced the evolution of these genes across diverse bacterial taxa. Notably, the cfr(C) gene was detected in 11 bacterial species following antimicrobial treatment, with mutation patterns characterized in Enterococcus faecalis, Klebsiella pneumoniae, Ruthenibacterium UN-1, and four unclassified species. In total, 29 ARG subtypes across eight types were identified in 13 known, five unknown, and 18 unclassified species, allowing us to trace their evolution routes. In addition, we detected a total of 309 horizontal gene transfer (HGT) events, in which several genes like folE and queE were frequently involved. The products of these genes are known to enhance the ability of the recipient bacterial strains to repair DNA damage and maintain genomic stability, especially following prolonged antibiotic treatment. Comparison between isolated strain genomes (IS-KP1) and single-cell analysis confirmed the presence of at least two K. pneumoniae strains in the patient, with one exhibiting a larger extent of involvement in ARG co-evolution. This strain was found to contain the cfr(C) and fosXCC genes, which were absent in IS-KP1. Klebsiella strains were also found to participate actively in HGT events. In conclusion, the study identified a wide range of ARGs and HGT events within the microbiome. The detection of K. pneumoniae strains with distinct ARG evolution patterns underscores the gut microbiome's adaptability to environmental changes. These findings facilitate the development of novel antimicrobial strategies by fine-tuning the gut microbiome composition.IMPORTANCEThis study highlights the power of single-cell sequencing to unravel the diversity and dynamics of the gut microbiome during antibiotic treatment in a patient with acute cerebral hemorrhage. By identifying antibiotic resistance genes (ARGs) in both known and unclassified bacterial species, we reveal the intricate evolution and horizontal transfer of resistance traits across taxa. The discovery of distinct ARG patterns, including the emergence of the cfr(C) gene in multiple species and its co-evolution in K. pneumoniae, underscores the gut microbiome's adaptability to antimicrobial pressures. These findings provide critical insights into the mechanisms driving resistance dissemination and offer potential pathways for developing precision microbiome-based therapies to combat antibiotic resistance.