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At least 19 recordsLinked to original sources

Genomic landscape of drug response reveals mediators of anthelmintic resistance.

Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Ivermectin↗

In vitro microbiological characterization of novel cyclic homopentapeptides, CP-101,680 and CP-163,234, for animal health use.

Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'-dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were identified as novel antibacterial agents for the treatment of animal disease, especially for livestock respiratory disease. The in vitro microbiological characterization of both CP-101,680 and CP-163,234 was carried out using their parent compounds, viomycin and capreomycin, as controls. This characterization included antibacterial spectrum, influence of media, inoculum size, pH, EDTA, polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition, and time-kill kinetics. Our results indicated that the capreomycin analog, CP-163,234, showed slightly improved in vitro potency over the viomycin analog, CP-101,680. Both analogs showed very potent cell-free protein synthesis inhibition activity and were bactericidal against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP-163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re-growth was observed after 24 hours incubation at both concentrations of CP-101,680.

Animal Diseases↗

Gut metagenome and plasma metabolome profiles in older adults suggest pyruvate metabolism as a link between sleep quality and frailty.

Poor sleep quality is associated with increased frailty in older adults, but the role of the gut microbiome in this relationship remains unclear. Here, gut metagenome and plasma metabolome were profiled in 1,225 individuals aged 62-96 years. Poor sleep quality was associated with reduced abundances of potential probiotics such as Faecalibacterium prausnitzii and elevated abundances of pathobionts. A gut microbiome sleep quality index (GMSI) was developed to quantify microbial balance related to better sleep quality; higher GMSI scores were inversely associated with frailty and related clinical traits. Pyruvate metabolism emerged as a key microbial pathway linking sleep quality to frailty, with features such as F. prausnitzii abundance and microbial pyridoxal 5'-phosphate biosynthesis implicated in this connection. These findings deepen our understanding of microbiome-metabolome pathways related to sleep quality and frailty in aging and provide a valuable resource for future longitudinal and interventional studies.

Humans↗

Multilevel regulation of c-di-GMP biosynthesis by cAMP signaling increases Shigella sonnei fitness and pathogenicity in response to bile salts.

It was previously demonstrated that intestinal pathogens have evolved different mechanisms to enhance their infection and colonization in the intestines of hosts. However, it is unclear how Shigella effectively survives in the presence of bile salts. Here, we report that the biofilm formation and pathogenicity of S. sonnei are induced by primary bile salts through the two-component system EvgS/EvgA. The response regulator EvgA controls the transcription of the cyclic AMP synthase-encoding gene. Furthermore, the effector protein CRP of the cyclic AMP (cAMP) signal not only positively controls the transcription of ydeH, a gene encoding cyclic di-GMP (c-di-GMP) synthase, but also forms a complex with YdeH to improve its catalytic production of c-di-GMP. Additionally, interacting with YdeH enhances the ability of CRP to bind to the promoter of ydeH. Our work provides insights into how S. sonnei utilizes cascade amplification of c-di-GMP to promote fitness and pathogenicity in response to primary bile salts.

Cyclic GMP↗

Genetic crosses reveal genomic loci responsible for virulence in Cryptosporidium parvum infection.

The relationship between parasite genotype and pathogenesis is largely unknown for Cryptosporidium, a leading cause of diarrheal disease in children. An array of parasites with similar genomes produces varied disease outcomes in different hosts. Here, we isolate and characterize Cryptosporidium parvum strains that show marked differences in virulence and persistence in mice. Taking advantage of the sexual life cycle of this eukaryotic pathogen, we use genetic crosses to discover the underlying chromosomal loci. Whole-genome sequencing and bulk segregant analysis of infection-selected progeny mapped three loci on chromosomes 2, 6, and 7 associated with the ability to colonize and persist in mice and the positions of drug resistance genes. The chromosome 6 locus encodes the hyper-polymorphic surface glycoprotein GP60. Reverse genetic studies in both parental strains demonstrate that GP60 controls parasite burden and virulence, but not persistence, and reveal the dominance of the less virulent allele, suggesting it restricts virulence.

Cryptosporidium parvum↗

Bacterial metabolite patterns of infants receiving multi-strain probiotics and risk of late-onset sepsis.

The effect of multi-strain probiotics containing Bifidobacterium longum (B. longum) on late-onset sepsis (LOS) risk in very-low-birth-weight infants (VLBWIs; birth weight < 1,500 g) remains uncertain. In a single-center study, we analyzed intestinal metagenome and metabolome data in VLBWIs during the period of highest vulnerability of LOS. Using a unit's policy change to routinely administer B. longum subspecies infantis plus Lactobacillus acidophilus as natural experiment, we compared 97 infants (including 38 LOS cases) after change with 78 infants (including 32 LOS cases) before. Probiotic supplementation was associated with more beneficial bacteria and reduced abundance of nosocomial pathobionts, such as Klebsiella spp. Infants in the probiotic group had significantly lower concentrations of B. longum fermentation products prior to sepsis diagnosis than matched non-LOS cases (acetate: padj = 0.0049; lactate: padj = 0.048). Modulation of the gut metabolic milieu is an interesting target for LOS prevention.

Humans↗

Expansion of secreted cystine knot proteins reveals virulence factors in the human fungal pathogen Histoplasma.

Identifying fungal secreted factors that influence host infection remains a key challenge in microbial pathogenesis. While secreted effectors, particularly small cysteine-rich proteins, are well characterized in plant fungal pathogens, their counterparts in mammalian pathogens are understudied. We apply criteria from plant fungal effectors to the mammalian fungal pathogen Histoplasma, yielding a set of putative effectors highly enriched for knottins, proteins that adopt a distinctive cystine knot fold. Using an algorithm, we further identify 25 putative knottins in the Histoplasma genome, revealing a significant expansion of knottin genes. Knottin domains are found in diverse molecules but play an unknown role in virulence. Functional studies of individual Histoplasma knottins demonstrate their critical roles in intracellular survival and host cell lysis during macrophage infection as well as virulence in vivo. These findings highlight the importance of knottins in fungal pathogenesis and suggest their broader relevance for discovering conserved mechanisms of host manipulation.

Histoplasma↗

Health-associated key gut microbiota drives the variation in community metabolic interactions in non-human primates.

Gut microbiota often undergo metabolic cross-feeding and resource competition. However, our understanding of global variations in these interactions and their implications for host health remain elusive. By analyzing a microbial genome catalog from 841 fecal metagenomes across 53 primate species worldwide, we identified key microbiota assigned to two taxa, i.e., Bacillota_A and Pseudomonadota, which well predicted the trade-off of community-level interaction types between metabolic competition and cooperation. Specifically, Bacillota_A species were inherently competitive and amino acid auxotrophic and typically found in anaerobic habitats. In contrast, members of Pseudomonadota were inherently cooperative, siderophore producers, and more abundant in aerobic conditions. Random forest models successfully distinguished unhealthy gut samples from healthy samples through the key competitive and cooperative microbiota, suggesting potential links between community metabolic interactions and host health. Together, this study enhances our mechanistic understanding of microbial interaction dynamism within complex gut ecosystems, offering new targets for understanding host health.

Animals↗

A deep metagenomic atlas of Qinghai-Xizang Plateau lakes reveals their microbial diversity and salinity adaptation mechanisms.

The Qinghai-Xizang Plateau (QXP), harboring the planet's highest density of plateau lakes, offers an exceptional biogeographic environment for studying extremophilic microbial communities and their adaptation to salinity. Through deep metagenomic sequencing, we construct the Qinghai-Xizang Lake Sediment Genome (QXLSG) catalog, a high-resolution genomic catalog comprising 5,866 metagenome-assembled genomes (MAGs), 58.16 million non-redundant protein encoding genes, and 19,008 biosynthetic gene clusters. Notably, 80.78% of the 2,742 species-level MAGs represent undescribed taxa, significantly expanding the known microbial diversity. Salinity emerges as the primary environmental factor influencing microbial community. Functional annotation highlights that the "salt-out" strategy, particularly the uptake of glycine betaine, is the main mechanism for salinity tolerance. This strategy is prevalent in both hypersaline lake communities and the dominant microbial phyla. Overall, this study provides a crucial genetic resource for future bioprospecting and deepens our understanding of the fundamental mechanisms of microbial adaptation to extreme saline environments.

Lakes↗

Diverse defense systems and prophages in human-associated Bifidobacterium species reveal coevolutionary "arms race" dynamics.

Bacteria of the genus Bifidobacterium are pivotal for human health, especially in early life, where they dominate the gut microbiome in healthy infants. Bacteriophages, as drivers of gut bacterial composition, can affect bifidobacterial abundance. Here, we use a bioinformatics approach to explore direct interactions between human-associated Bifidobacterium spp. and prophages, as evidenced by their genomes. Analysis of 1,086 bifidobacterial genomes reveals the presence of complex systems that prevent viral invasion, with 34 defense systems and 56 subtypes detected, including several different CRISPR-Cas systems. CRISPR spacers target almost three-quarters of bifidobacteria-derived prophages, indicating dynamic interactions. At least one prophage is present in &#x223c;67% of strains, with phages exhibiting high genomic diversity and evidence of historical recombination. These prophages encode various defense and anti-defense systems, such as anti-CRISPR genes and restriction-modification mechanisms. Overall, this investigation reveals that coevolutionary "arms race" dynamics drive genomic diversity in both bifidobacteria and their phages.

Prophages↗

From sporulation to village differentiation: The shaping of the social microbiome over rural-to-urban lifestyle transition in Indonesia.

Despite established roles in human health and profound global diversity, microbiome datasets remain biased toward Western urban cohorts, with especial under-representation of Southeast Asia. Here, we present a gut microbiome dataset from 116 Indonesians spanning transitional hunter-gatherer, rural agricultural, and urban lifestyles. We identify 1,304 species and 3,258 subspecies by assembling 11,070 metagenome-assembled genomes, revealing substantial species- (15%) and subspecies- (50%) level novelty. Novel taxa are rare, often village specific, and depleted for sporulation genes, revealing a link between bacterial physiology, transmission, prevalence, and discovery. We identify rural-to-urban clines across multiple levels of biological organization, from species abundance to microbiome composition and diversity. Furthermore, between-community, but not within-community, diet variation is strongly predictive of microbiome composition, suggesting that microbiome divergence is driven by community-level differences. Our work highlights the interplay of host lifestyle, population structure, and bacterial physiology in shaping microbiome diversity and biogeography, at the key scale of human communities.

Humans↗

Genomic epidemiology of dengue virus 2 and 3 reveals repeated introductions and exportations of several lineages in Colombia.

Dengue fever, a major mosquito-borne viral disease, is transmitted by Aedes mosquitoes and poses a significant global health burden. Despite extensive research, the spatiotemporal dynamics of dengue virus (DENV) lineages in Colombia remain understudied. Here, we analyze 11,443 complete genome sequences from Colombia and the Americas to map the genomic epidemiology of DENV-2 and DENV-3. Phylogeographic reconstruction revealed multiple independent introductions and exportations of the DENV-2 II and III lineages, as well as the DENV-3 lineage III_C.2, underscoring Colombia's critical role as both a source and a sink of viral traffic within the Americas. Antigenic profiling demonstrated distinct clustering of emergent lineages in antigenic space, consistent with immune-escape-driven turnover. These results highlight the necessity of sustained, high-resolution genomic surveillance to guide targeted public health interventions and mitigate dengue transmission across the region.

Dengue Virus↗

Species and strain sharing in the vaginal microbiome of mothers and their adult daughters.

The vaginal microbiome is key for women's health. However, its establishment, interindividual variation and dynamics remain poorly understood. Here, we investigate bacterial relatedness at species and strain level in adult mother-daughter pairs from the large-scale citizen-science program Isala. Using metagenomic sequencing with quality control including 16S rRNA profile comparison, along with targeted culturing, we assess intergenerational microbiome sharing. At species level, daughters' vaginal microbiomes are significantly more similar to their mothers' than to those of unrelated mothers, with a strong mother-daughter correlation in Lactobacillus crispatus dominance. Strain-level analyses of metagenomes and isolate genomes reveal intraspecies diversity in L. crispatus, with up to two strains observed within the same host, and support intergenerational vaginal bacteria sharing. SNV counts in shared L. crispatus strains show no correlation with daughters' ages. Together, these findings suggest that maternal transmission, host factors, and (shared) environment collectively shape the vaginal microbiome, providing fundamental ecological insights into vaginal microbiome dynamics and perspectives toward lactobacilli-based applications.

CP: microbiology↗

From colonization to infection: Genomic evolution of Clostridioides difficile pathogenesis.

Clostridioides difficile is a spore-forming, toxin-producing anaerobe that is a leading cause of healthcare-associated infections. Its success as a pathogen reflects a complex interplay between bacterial evolution, virulence regulation, ecological adaptation, environmental selection, and host susceptibility. Comparative genomics has revealed deep C. difficile lineage diversification, driven by mobile genetic elements and selective pressures from antibiotics and host environments. These events affect strain-specific virulence by shaping the organization and regulation of the pathogenicity toxin loci, metabolic adaptations for nutrient utilization, and enhanced spore resilience. This review integrates evolutionary and genomic perspectives to illustrate how adaptive diversification has sculpted C. difficile pathogenesis and epidemic success.

CP: microbiology↗

Spontaneous lytic reactivation drives a persistent B cell-vector pathway for epithelial dissemination of the Epstein-Barr virus.

The Epstein-Barr virus (EBV) establishes lifelong B cell infection via oral transmission; however, it paradoxically drives carcinomas in anatomically distant organs with striking geographic disparities. While genomic studies frequently link specific EBV variants to these epithelial cancers, the mechanisms bridging ubiquitous infection to distant, strain-dependent malignancies remain largely unresolved. Using an induction-free primary B cell system, we identify a circulating B cell-vector pathway driving immortalized epithelial dissemination. We demonstrate that B cells infected with carcinoma-associated strains exhibit markedly higher epithelial transmission compared with those carrying lymphoid strains. This contact-dependent process requires spontaneous lytic reactivation, viral DNA replication, and de novo virion production. Crucially, those infected B cells retain their transmission capacity for months, supporting sustained epithelial seeding. Mechanistically, entry requires gH/gL engagement of EphA2/desmocollin-2 (DSC2), with actin- and PI3K-dependent endocytosis. These findings define a lytic-coupled, receptor-dependent pathway by which the EBV exploits B cells to access the epithelium, offering a mechanistic framework for understanding strain tropism and host-virus interactions.

B cell vector↗

In vitro microbiological characterization of novel macrolide CP-163,505 for animal health specific use.

A novel 16-membered-ring macrolide agent (CP-163,505, a reductive amination derivative of repromicin) was identified as an antibacterial against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae, important etiological agents of livestock respiratory disease. In vitro MIC50/90 analysis revealed that CP-163,505 was more potent (4x) than tilmicosin against P. multocida, and equivalent to tilmicosin against P. haemolytica and A. pleuropneumoniae. In time kill kinetic studies, CP-163,505 showed bactericidal activity against P. haemolytica, P. multocida and A. pleuropneumoniae and bacteriostatic activity against E. coli at 8 times its MIC. In vitro, CP-163,505 was more potent in alkaline pH (16 approximately 32 x ) and less potent in the presence of excess cations (Mg+2 and Ca+2, 4x). EDTA and PMBN increased CP-163,505 potency against E. coli (4x) but not against the other species. Similar results were obtained with erythromycin A and tilmicosin, which were used as controls. From our data, we hypothesize that Pasteurella and Actinobacillus have an outer membrane significantly different from that of the typical enteric Gram-negative bacterium E. coli.

Actinobacillus pleuropneumoniae↗

Teicoplanin binding in plasma following administration of increasing intravenous doses to healthy volunteers.

Teicoplanin is a new long half-life glycopeptide antibiotic active against Gram-positive bacteria. Binding to plasma protein can significantly affect the pharmacokinetics of drugs with low extraction ratio, such as teicoplanin; clearance, volume of distribution and half-life of the drug change as the fraction of drug unbound (fu) varies, with obvious clinical implications. In this study, the linearity of teicoplanin binding to plasma protein was studied in healthy volunteers receiving single increasing intravenous doses of 15, 20 and 25 mg/Kg teicoplanin. Unbound fraction of teicoplanin in human plasma was determined by ultrafiltration. Unbound and total teicoplanin concentrations, Cu and Cp, were measured by microbiological assay. The results indicate that Cu was linearly correlated to Cp in the Cp range from 7 to 280 mg/L, according to the following regression model: Cu = 0.105 Cp - 0.234 (r = 0.9947) in which the coefficient 0.105 represents the average fu. Individual estimates of fu were calculated for every sample as the ratio between Cu and Cp; mean fu values were 0.100 +/- 0.002 (SE), 0.101 +/- 0.002 and 0.097 +/- 0.002, after 15, 20 and 25 mg/Kg, respectively. No statistical difference was found between groups. We conclude that the binding of teicoplanin to plasma protein is linear up to about 300 mg/L and fu value is not dose-dependent from 15 to 25 mg/Kg dose. These conclusions are in keeping with the observation that the pharmacokinetics of teicoplanin is linear in the dose range from 15 to 25 mg/Kg. These estimates of teicoplanin unbound fraction using ultrafiltration are also in agreement with previously reported values obtained by equilibrium dialysis. A mathematical model is proposed to predict changes of fu as the total plasma concentration increases.

Anti-Bacterial Agents↗

[Significance of antibacterial therapy of Chlamydophila pneumoniae infection in patients with bronchial asthma].

AIM: To study effects of eradication of Chlamydophila pneumoniae CP) infection in bronchial asthma (BA) on BA course and changes in quality of life (QOL) in BA patients. MATERIAL AND METHODS: 194 BA patients in clinical remission participated in the trial. Microbiological diagnosis of asymptomatic CP infection was made serologically (ELISA, indirect enzyme immunoassay) using polymerase chain reaction. Clinical and biochemical tests, assessment of pulmonary ventilation function, QOL by AQLQ during 6-week antimicrobial therapy were made in 56 patients. RESULTS: Patients with stable BA had high frequency of serological signs of clinically asymptomatic CP infection (52%) deteriorating BA symptoms and QOL. Antibacterial therapy of latent CP infection with azitromycin significantly improved BA course and QOL of BA patients. CONCLUSION: When laboratory tests detect CP infection in patients with long-term course of BA, especially in smoking males with moderate and severe BA it is clinically valid to prescribe addition of azitromycin to basic antiinflammatory treatment of BA.

Anti-Bacterial Agents↗