Establishment of an aqueous environment as a novel mechanism of bacterial pathogenesis

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Establishment of an aqueous environment as a novel mechanism of bacterial pathogenesis PI: HE, Sheng Yang; Michigan State University Project summary Many bacterial pathogens of plants and mammals, including humans, use the highly conserved type III secretion system (T3SS) to inject “effector proteins” into the host cell as an important paradigm of pathogenesis. The long-term goal of this project is to characterize a newly discovered T3SS-mediated virulence strategy by which bacterial pathogens create an aqueous extracellular environment in host tissues. In nature, many host-pathogen and host-microbiome interactions occur in air-exposed/connected host organs/tissues (e.g., epidermis/skin and gas-exchange organs including respiratory systems and plant leaves) in which water availability is limited and/or variable. Because microbes generally require a moist/aqueous/mucous environment to survive and proliferate, it is not well understood whether microbes actively establish an infection-conducive aqueous environment in host organs. In humans, malfunction of aquaporins has been associated with infectious diseases, kidney malfunction and even cancer development and there is an emerging link between aquaporin- mediated water transport and pathogenesis of enteropathogenic Escherichia coli. However, cause-effect relationships often remain unclear. In the past 25 years, the Principal Investigator’s lab has used the model Arabidopsis thaliana – Pseudomonas syringae interaction to discover and characterize T3SS-mediated bacterial infection mechanisms. By taking advantage of the genetic tractability of Arabidopsis and a well-characterized T3SS effector repertoire in P. syringae, the PI’s lab recently discovered a critical role of an aqueous environment in bacterial pathogenesis. In this application, three specific aims are proposed to test the central hypothesis that, by altering (i) ARF-GEFMIN7-dependent vesicular traffic and (ii) phosphorylation of aquaporins involved in regulating water transport across host plasma membrane, P. syringae disrupts water homeostasis across the host plasma membrane, resulting in an aqueous extracellular environment as an important mechanism of pathogenesis. Aim 1 will determine the role of ARF-GEFMIN7-associated host proteins in regulating vesicular traffic of aquaporins and extracellular water. Aim 2 will investigate how P. syringae T3SS effector proteins target ARF-GEFMIN7- associated vesicle traffic and aquaporins to induce an aqueous extracellular environment. Aim 3 will elucidate how activation of host immunity prevents the virulence actions of P. syringae T3SS effectors as a novel dimension of the host innate immune response. Contemporary methods in molecular genetics, cell biology, biochemistry and microbial pathogenesis will be used in this study. Successful completion of this research will significantly advance our understanding of a newly discovered bacterial virulence mechanism and its interplay with host innate immunity. As many host-microbe interactions occurs in air-connected host organs/tissues, in which water availability is restricted, it is hoped that this original research will stimulate studies to broadly examine water regulation in other host-pathogen interactions, and, in the long- term, facilitate the development of innovative and broadly applicable measures for controlling infectious diseases in diverse eukaryotic hosts, including plants, animals and humans.