Intracellular bacterial pathogens, including some select agents and emerging pathogens, are known to modify host cells to allow for survival and propagation. Host cell phenotypic changes commonly result in dysregulation of function that leads to disease. Bacterial toxins interfere with a number of host physiological processes.
Only recently, toxins that are delivered into the host cell and lead to functional alterations at the nuclear interface were described, including the AnkA protein of Anaplasma phagocytophilum, which we have shown to affect host cell epigenetics, transcription and function. The long-term objective of the proposed research is to develop a mechanistic understanding of the pathogenic process by which bacterial nuclear toxins regulate host cell function.
Because many of the host cell functions are modified upon intracellular bacterial infection, we hypothesize that the host cell is reprogrammed upon infection through host epigenetic alterations mediated by nuclear toxins. To test this hypothesis, we will use the A. phagocytophilum / AnkA - neutrophil interactions model to pursue the following specific aims:
1. To demonstrate that host neutrophils are reprogrammed upon ehrlichial infection.
2. To demonstrate that ehrlichial nuclear toxins induce host cell reprogramming.
3. To identify novel nuclear ehrlichial toxins involved in host cell reprogramming.
Information obtained will identify mechanisms of pathogenicity possibly conserved among divergent groups of bacteria mediated by nuclear toxins, improving our understanding of the molecular basis of bacterial pathogenesis and manipulation of host cell function, and identify targets for potential therapeutic intervention. As a career development grant, it will allow the candidate to expand his skills beyond microbial pathogenesis by studying bacterial toxins in the context of fundamental biological processes such as cell differentiation. The data obtained from this project will serve as basis for new projects and will create new opportunities for extramural research support.
Jose Carlos Garcia-Garcia