Cellular homeostasis is important for retaining cellular viability and functions, and often manipulated by bacterial pathogens as an effective target for remodeling the host environment for colonization. Helicobacter pylori, a human gastric pathogen that impacts more than a half the human population as the only recognized biological carcinogen, colonizes the highly acidic human gastric environment by modulating host cellular homeostasis. Vacuolating cytotoxin A (VacA) is a pore-forming exotoxin of H. pylori, that, once secreted, enters the host cells and targets mitochondria. Previous studies revealed that VacA supports H. pylori colonization by altering host energy metabolism, specifically, by collapsing the proton gradients that are required for mitochondrial energy production. However, how such VacA cellular actions alter host cell biology during H. pylori infection has not been well understood, and was the major gap in knowledge addressed in this dissertation. Here, the studies revealed that VacA-induced metabolic stress is sensed by host cells in a manner mediated by mTORC1, a central metabolic sensor in mammalian cells. VacA-mediated inhibition of mTORC1, which is also a major metabolic regulator, indicated a global metabolic shift from a biosynthetic state to a catabolic state, as manifested by two major cellular changes; 1) induction of autophagy, a catabolic recycling mechanism that can generate extra carbon and energy sources to support a restoration of the metabolic balance, and, 2) inhibition of host protein synthesis. Furthermore, the studies unexpectedly revealed that cellular amino acids, which are the building blocks for de novo protein synthesis, also often utilized as carbon and energy sources at mitochondria, were depleted by H. pylori infection in a VacA-dependent manner. In addition, the amino acid deficiencies within VacA-intoxicated cells were largely attributed to the loss of cellular capabilities of importing extracellular amino acids in an energy-dependent manner, and the continuous consumption of amino acids at mitochondria resulted in the depletion of intracellular amino acid pools. Lastly, the studies provided the premise for evaluating how VacA manipulation of host metabolism alters host cell biology during H. pylori infection. In particular, reduction in host production of mucus proteins, key innate immune factors secreted to repel approaching pathogens, could possibly result in a VacA-dependent manner during H. pylori infection. In conclusion, the studies in this dissertation investigated how VacA could contribute to H. pylori infection biology, and revealed that VacA induces a global metabolic shift towards a less biosynthetic and more catabolic state, which could alter host effectiveness to respond to H. pylori infection. I speculate that future investigation on how the VacA-dependent metabolic shift within host cells alters host capacity to produce immune/protective factors against infection will extend our understanding in microbial infection biology, and, may contribute to developing more effective and comprehensive therapeutics against H. plyori infection
