My laboratory uses Salmonella as a highly tractable model organism to delineate the mechanisms through which pathogens manipulate host cells to either grow within them or exploit them as vehicles for dissemination to deeper tissue. There are two questions in my laboratory:
1) How are human proteins subverted by pathogens to facilitate intracellular growth?
To begin to answer this question, we designed a fluorescence based high throughput RNA interference assay and screened the entire human genome for host factors that allow intracellular Salmonella growth. In all, we identified 252 human proteins, that we are beginning to characterize, that permit Salmonella growth within infected, human cells. The long-term goal of this project is to advance our understanding of the Salmonella/macrophage paradigm, which may provide us with insight into the underlying shared logic through which numerous pathogens manipulate host cells. Also, these host susceptibility factors can potentially be exploited as a novel class of anti-microbial targets and finally can illuminate many aspects of fundamental host cell biology.
2) Through what mechanisms do intracellular pathogens disseminate within hosts to cause serious, systemic disease?
The long-term goal of this project is to develop and test comprehensive, global models that account for reverse transmigration and its regulation. Reverse transmigration is a naturally occurring process in which dendritic cells traverse endothelium in the basal to apical direction. While Salmonella can spread from the gastrointestinal tract (GI) to the bloodstream within these cells, it is conventionally thought to be passive on the part of the microbe. We have uncovered evidence however, indicating that Salmonella can actively parasitize reverse transmigration to expedite bacterial colonization of internal organs. This is likely relevant to the spread of numerous pathogenic microbes not only the GI tract, but also from lung tissue and the oral mucosa to the systemic circulation. Reverse transmigration also functions in the invasion of the bloodstream by some cancerous cells and in excessive inflammation disorders such as autoimmune and graft versus host disease, which piques our long-term interest in designing drugs that either inhibit or augment the process.