Jorge E. Galan
Board Member: 2001 - 2005
Mechanisms of Bacterial Pathogenesis
Our research interests center on the interaction of bacterial pathogens with their hosts. In particular, we are studying the molecular mechanisms by which Salmonella spp. interact with their host cells. Salmonella spp. are enteric pathogens that cause a great variety of diseases in a large number of hosts. The type of disease that these organisms can cause vary significantly depending on the infecting Salmonellae as well as on the infected host and may range from mild gastroenteritis (i. e. food poisoning) to more life threatening, systemic forms such as typhoid fever. An essential feature of the pathogenicity of Salmonella is their ability to engage the host cell in a two-way biochemical interaction or cross-talk. This cross-talk leads to responses from both the bacteria and the host-cell. Salmonella responds to the presence of the host-cell by activating a specialized protein secretion system termed Type III or contact dependent which directs the export of several proteins. These proteins transiently assemble in appendage-like structures called Invasomes and subsequently trigger host cell signal transduction pathways leading to a variety responses. These responses are strictly dependent on the type of infected cell. In non-phagocytic cells, Salmonella induces profound cytoskeletal rearrangements and changes in the host-cell plasma membrane that closely ressemble the membrane ruffles induced by a variety of agonists such as various hormones and growth factors as well as the activation of cellular oncogenes. Membrane ruffling is accompanied by macropinocytosis which ultimately leads to bacterial internalization. A time-lapse video sequence of Salmonella-induced membrane ruffling can be seen in our movie page. Another response induced by Salmonella in epithelial cells is the activation of various transcription factors which ultimately result in the production of pro-inflammatory cytokines such as IL-8. This is an important event in Salmonella pathogenesis as one of the hallmarks of salmonellosis is the stimulation of a profuse inflammatory diarrhea. In macrophages, on the other hand, Salmonella induces cytotoxic effects characterized initally by a rapid inhibition of membrane ruffling and macropinocytosis and subsequently by the induction of apoptotic cell death. A time-lapse sequence of Salmonella-induced macrophage cytotoxicity can be seen in our movie page.