Biology subjects

Worley, J. N.

Publications and source records attributed to Worley, J. N..

4 recordsLinked to original sources

bioRxiv2024

Approaching pathogenic Clostridia from a One Health perspective

Spore-forming pathogens have a unique capacity to thrive in diverse environments, and with temporal persistence afforded through their ability to sporulate. These behaviors require a One Health approach to identify critical reservoirs and outbreak-associated transmission chains, given their capacity to freely move across soils, waterways, foodstuffs, and as commensals or infecting pathogens in human and veterinary populations. Among anaerobic spore-formers, genomic resources for pathogens including C. botulinum, C. difficile, and C. perfringens enable our capacity to identify common and unique factors that support their persistence in diverse reservoirs and capacity to cause disease. Publicly available genomic resources for spore-forming pathogens at NCBIs Pathogen Detection program aid outbreak investigations and longitudinal monitoring in national and international programs in public health and food safety, as well as for local healthcare systems. These tools also enable research to derive new knowledge regarding disease pathogenesis, and to inform strategies in disease prevention and treatment. As global community resources, the continued sharing of strain genomic data and phenotypes further enhances international resources and means to develop impactful applications. We present examples showing use of these resources in surveillance, including capacity to assess linkages among clinical, environmental, and foodborne reservoirs and to further research investigations into factors promoting their persistence and virulence in different settings.

genomics↗

bioRxiv2023

Central in vivo mechanisms by which C. difficile's proline reductase drives efficient metabolism, growth, and toxin production

Clostridioides difficile (CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentations of amino acids, with proline being a preferred reductive substrate. To investigate the in vivo effects of reductive proline metabolism on C. difficiles virulence in an enriched gut nutrient environment, we evaluated wild-type and isogenic{Delta} prdB strains of ATCC43255 on pathogen behaviors and host outcomes in highly susceptible gnotobiotic mice. Mice infected with the{Delta} prdB mutant demonstrated extended survival via delayed colonization, growth and toxin production but ultimately succumbed to disease. In vivo transcriptomic analyses demonstrated how the absence of proline reductase activity more broadly disrupted the pathogens metabolism including failure to recruit oxidative Stickland pathways, ornithine transformations to alanine, and additional pathways generating growth-promoting substrates, contributing to delayed growth, sporulation, and toxin production. Our findings illustrate the central role for proline reductase metabolism to support early stages of C. difficile colonization and subsequent impact on the pathogens ability to rapidly expand and cause disease.

microbiology↗

bioRxiv2020

Predictive regulatory and metabolic network models for systems analysis of Clostridioides difficile

Though Clostridioides difficile is among the most studied anaerobes, the interplay of metabolism and regulation that underlies its ability to colonize the human gut is unknown. We have compiled public resources into three models and a portal to support comprehensive systems analysis of C. difficile. First, by leveraging 151 transcriptomes from 11 studies we generated a regulatory model (EGRIN) that organizes 90% of C. difficile genes into 297 high quality conditional co-regulation modules. EGRIN predictions, validated with independent datasets, recapitulated and extended regulons of key transcription factors, implicating new genes for sporulation, carbohydrate transport and metabolism. Second, by advancing a metabolic model, we discovered that 15 amino acids, diverse carbohydrates, and 10 metabolic genes are essential for C. difficile growth within an intestinal environment. Finally, by integrating EGRIN with the metabolic model, we developed a PRIME model that revealed unprecedented insights into combinatorial control of essential processes for in vivo colonization of C. difficile and its interactions with commensals. We have developed an interactive web portal (http://networks.systemsbiology.net/cdiff-portal/) to disseminate all data, algorithms, and models to support collaborative systems analyses of C. difficile.

systems biology↗

bioRxiv2020

The mechanisms of in vivo commensal control of Clostridioides difficile virulence

We define multiple mechanisms by which commensals protect against or worsen Clostridioides difficile infection. Leveraging new systems-level models we show how metabolically distinct species of Clostridia modulate the pathogens colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survived infection while mice colonized with the butyrate- producer, Clostridium sardiniense, more rapidly succumbed. Systematic in vivo analyses revealed how each commensal altered the gut nutrient environment, modulating the pathogens metabolism, regulatory networks, and toxin production. Oral administration of P. bifermentans rescued conventional mice from lethal C. difficile infection via mechanisms identified in specifically colonized mice. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile infections using systems biologic approaches to define host-commensal-pathogen interactions in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/894915v2_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@15a6940org.highwire.dtl.DTLVardef@b4290borg.highwire.dtl.DTLVardef@1f2af49org.highwire.dtl.DTLVardef@1d1e6b9_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

microbiology↗