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https://www.med.unc.edu/microimm/directory/adam-rosenthal-phd/ |
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Uncovering the role of cell-cell heterogeneity in infection
During infection individual cells of a bacterial pathogen can co-occur in distinct physiological states. Such phenotypic heterogeneity has been recently reported in landmark virulence processes including expression of toxin genes, sporulation, genetic exchange, cell-attachment, and resistance and persistence to antibiotics and can provide community benefit to the pathogen. The focus of our research is to understand the extent and role of phenotypic heterogeneity in infection and the genetic programs that control differentiation and switching dynamics between cellular states. This understanding can then be used to devise therapeutic interventions that specifically target virulent cells.
Traditional “bulk-level” measurements of bacterial pathogens average the signal of specialized cells in the population and therefore mask their individual physiological role. Therefore, high-throughput single cell studies of pathogenic heterogeneity are needed to understand how a community of bacterial cells collectively organize infection and coordinate virulence. However, despite the importance of cellular heterogeneity in infection, there is a lack of high-throughput methods to assess genome-wide heterogeneity in bacteria at the single-cell level.
To address these challenges, we recently developed the first microfluidic technique that achieves high quality bacterial single-cell transcriptomics. This technique overcomes many technical difficulties inherent to bacterial single cell RNA-seq including the lack of mRNA polyadenylation, the presence of diverse microbial cell walls, and the high rRNA loads and short mRNA half-life of bacterial mRNA. Using this tool and other methods there are fundamental questions our lab will address: What are the mechanisms and signals that activate cells in a benign state to transform into a virulent phenotype? Which particular virulence programs and metabolic physiologies are expressed in specialized cells, and can we use this knowledge to predict perturbations that reduce toxicity? Can we uncover the dynamics and mechanisms that regulate the differentiation of particular cells into the pathogenic states? Can we learn how single-bacterial cells interact with other bacterial species in the microbiome and with the host, especially the host immune system?
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