(6cp) Understanding the Influence of the Host Environment on Phenotypic Heterogeneity of Bacteria for Development of Effective Therapeutics

Phenotypic heterogeneity in bacterial populations is a common mechanism by which bacteria survive environmental stress. For example, bacterial persisters have the ability to tolerate extraordinary levels of antibiotics due to their phenotypic state. Unlike the resistant bacteria that arise from heritable mutations, persisters are genetically identical to their antibiotic non-tolerant progenies. Persisters are a significant public health problem because they are enriched in biofilms and have been hypothesized to underlie the proclivity of biofilm infections to relapse. Though the medical relevance of persisters is associated with infection sites in the human body, persistence has largely been studied in vitro using synthetic media. Pathogens associated with persistent bacterial infections such as tuberculosis, gastrisis, cystic fibrosis and urinary tract infections are developed in host environments including liver, lung and epithelial cells, which are far more complex environments than that attainable in vitro. Studies regarding the interaction between persisters and host environment are widely missing, and therefore, it is still unknown how host environments influence bacterial physiology with regard to persistence. Based on the expertise I have gained during my postdoctoral and graduate training, including both computational and experimental experiences for both mammalian and bacterial systems, I am planning to study the effects of host conditions on persister levels and physiology, and develop experimental models including mammalian systems to analyze the effects of host-pathogen interactions on persistence. After establishing experimental models, persister physiology will be analyzed by genetic, biochemical, and flow cytometric assays to elucidate molecular mechanisms responsible for persistent state, which can form the basis of novel therapeutics for the treatment of chronic infections.