We are interested in understanding how two intracellular pathogens, Salmonella and rickettsiae, manipulate host cells. Salmonella typhimurium is an ideal model to understand the shared logic with which microbes manipulate host cells, as it combines the advantages of excellent genetics with tractable animal models of infection. We are interested in the ability of S. typhimurium to actively exploit the migratory properties of infected phagocytes and conversely the failure of the immune system to control the movement of such cells.

Salmonella is a gram negative, enteric bacterial pathogen that can infect diverse hosts including birds, reptiles and mammals. S. typhimurium causes a self-limiting gastroenteritis in humans whereas Salmonella typhi causes typhoid fever, a frequently fatal systemic disease. Salmonella infection is a major public health problem with Salmonella spp. causing more than one billion new human infections each year that lead to more than three million deaths, a problem exacerbated by the emergence of multi-drug resistant strains.

In addition to public health concerns, Salmonella is also studied because it is a model pathogen without parallel for understanding basic pathogenic mechanisms. Salmonella is able to invade eukaryotic cells and can evade detection and destruction by the immune system - traits that are essential to most human pathogens. Also, an excellent mouse model forSalmonella infection exists, allowing for the dissection of the complex interactions that occur between a pathogen and an intact mammalian immune system, and in our case, allows for the study of how a pathogen spreads within a host. This model is relevant to understanding serious, systemic infections of humans as S. typhimurium, the organism we study, causes typhoid fever in mice as S. typhi does in humans. Additionally, Salmonella is easily cultivated, is genetically tractable, and readily amenable to molecular biology manipulations.

We have recently discovered that Salmonella actively manipulates the migratory properties of certain host cells to expedite its colonization of its preferred sites of replication within its host. In essence, Salmonella can ‘hijack’ certain cells and ‘drive’ them places. We have identified one protein, SrfH, that Salmonella secretes into infected cells that is involved in ‘hijacking’ them and have determined that it binds the host TRIP6. TRIP6 can both activate and repress motility. We are interested in understanding on a mechanistic level how SrfH subverts TRIP6 to activate cellular motility. We know that additional secreted proteins are involved in ‘hijacking’ host cells and are interested in identifying them and characterizing them.

Rickettsiae are gram-negative bacteria that only grow within eukaryotic host cells. In nature, rickettsiae are maintained in a complex life cycle that involves transmission between arthropods and vertebrates. Humans are infected accidentally when they come in contact with arthropod vectors such as ticks, fleas, and lice or their excrement.

In addition to being intrinsically fascinating organisms, rickettsiae are also studied because two notoriously virulent species are classified as select agents with potential use as tools for bioterrorism. Ricekttsia prowazekii has previously been weaponized. According to the WHO’s estimate, if 50 Kg of aerosolized R. prowazekii was released in a bioterrorist attack, it would cause over 104,000 casualties. Currently, diagnosis of rickettsial infections is difficult and reliable vaccines do not exist. Additionally, there are only a few antibiotics available for the treatment of rickettsial infections.

Only a handful of rickettsial virulence factors have been identified because of the intrinsic difficulty in working with these obligate intracellular bacteria and their genetic intractability. Although Salmonella and rickettsiae are only distantly related, we have taken a similar approach toward studying their pathogenesis: the development of genetic systems to identify secreted proteins following by trying to figure out what these proteins do inside of host cells. We have just begun developing genetic tools to allow us to identify rickettsial secreted proteins. We have one secreted protein in hand that appears to interfere with MHC-I presentation of antigens to T cells, helping rickettsiae ‘hide’ from the immune system. We are currently trying to understand the mechanism of this down-regulation.