Biology subjects

Johnson, S. A.

Publications and source records attributed to Johnson, S. A..

3 recordsLinked to original sources

bioRxiv2018

Propionic acid enhances the virulence of Crohn’s disease-associated adherent-invasive Escherichia coli

The short chain fatty acid propionic acid (PA) is a bacteria-derived human intestinal antimicrobial and immune modulator used widely in Western food production and agriculture. Here we examine the effect of PA on the pathogenicity of the Crohns disease-associated microbe, adherent-invasive Escherichia coli (AIEC). Passage of AIEC through a murine model, where the low intestinal PA levels were increased to replicate those of the human intestine, led to the recovery of AIEC post-infection that had significantly increased virulence. These phenotypic changes, including increased adhesion to intestinal epithelial cells and biofilm formation, could be replicated in AIEC in vitro through exposure to PA alone. This in vitro exposure of AIEC to PA fundamentally changed AIEC virulence, with strains exposed to PA in vitro subsequently persisting at 20-fold higher levels in a murine model compared to non-exposed strains. RNA-sequencing identified the transcriptional changes in AIEC in response to PA with upregulation of genes involved in biofilm formation, stress responses, metabolism, membrane integrity and alternative carbon source utilisation. These PA induced changes in virulence could be replicated in a number of E. coli isolates from Crohns disease patients. Finally, removal of the PA selective pressure was sufficient to reverse these phenotypic changes. Our data indicate that exposure of AIEC to PA evolves bacteria that are both resistant to this natural human intestinal antimicrobial and increasingly virulent in its presence.\n\nImportanceExposure to propionic acid, an intestinal short chain fatty acid and commonly used antimicrobial in Western food production, induces significant virulence associated phenotypic changes in adherent-invasive Escherichia coli (AIEC).

microbiology↗

bioRxiv2017

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -- one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -- for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL). These data are available for download via the Gene Expression Omnibus (accession GSE101406), and web apps for interacting with this resource are available at https://clue.io/proteomics.\n\nHighlightsO_LIFirst-of-its-kind public resource of proteomic responses to systematically administered perturbagens\nC_LIO_LIDirect proteomic profiling of phosphosignaling and chromatin states in cells for 90 drugs in six different cell lines\nC_LIO_LIExtends Connectivity Map concept to proteomic data for integration with transcriptional data\nC_LIO_LIEnables recognition of unexpected, cell type-specific activities and potential translational therapeutic opportunities\nC_LI

systems biology↗

bioRxiv2017

Agrochemical pollution increases risk of human exposure to schistosome parasites

Roughly 10% of the global population is at risk of schistosomiasis, a snail-borne parasitic disease that ranks among the most important water-based diseases of humans in developing countries1-3. Increased prevalence, infection intensity, and spread of human schistosomiasis to non-endemic areas has been consistently linked with water resource management related to agricultural expansion, such as dam construction, which has resulted in increased snail habitat1,4-6. However, the role of agrochemical pollution in human schistosome transmission remains unexplored, despite strong evidence of agrochemicals increasing snail-borne diseases of wildlife7-9 and a projected 2- to 5-fold increase in global agrochemical use by 205010 that will disproportionately occur in schistosome-endemic regions. Using a field mesocosm experiment, we show that environmentally relevant concentrations of fertilizer, the common herbicide atrazine, and the common insecticide chlorpyrifos, individually and as mixtures, increase densities of schistosome-infected snails by increasing the algae snails eat (fertilizer and atrazine) and decreasing densities of snail predators (chlorpyrifos). Epidemiological models indicate that these agrochemical effects can increase transmission of schistosomiasis. Hence, the rapid agricultural changes occurring in schistosome-endemic regions11,12 that are driving increased agrochemical use and pollution could potentially increase the burden of schistosomiasis in these areas. Identifying agricultural practices or agrochemicals that minimize disease risk will be critical to meeting growing food demands while improving human wellbeing13,14.

ecology↗