My laboratory studies the enteric bacterial pathogen, Yersinia pseudotuberculosis, which causes gastroenteritis, mesenteric lymphadenitis and occasionally spreads systemically to organs in humans and other mammals, including mice. Pathogenic Yersinia spp. carry a virulence plasmid with genes encoding a type III secretion system and effector proteins, called Yops. The type III secretion system allows Yersinia to transport Yops directly from the cytoplasm of the mammalian cells where they disrupt mammalian cell functions. We have been investigating which Yops are needed for Y. pseudotuberculosis to colonize the GI tract and lymph tissues in a mouse model system of infection.

Given our current data, we think Yops function in three ways in the GI tract. First, Yops are needed for Y. pseudotuberculosis survival and colonization early after infection. In the absence of all five Yops, the numbers of Yersinia in the GI tract steadily decreases and soon are undetectable while the numbers of wildtype Y. pseudotuberculosis increase. However, in the absence of any one Yop, the bacteria colonize as efficiently or almost as efficiently as wildtype Yersinia. In the absence of both YopE and YopH, or YopO and YopH, the bacteria fail to colonize the GI tract. Thus YopH and, YopE or YopO, are required for GI tract colonization, suggesting that YopE and YopO function redundantly in the GI tract.

Second, while YopH and YopE are individually dispensable for colonization, each is necessary to induce weight loss and morphologically changes in the GI tract. This implies that either several signals must be induced to promote gastroenteritis or that YopE and YopH act in concert to induce gastroenteritis.

Third, in competition assays with wildtype Y. pseudotuberculosis, several of the Yops individually appear important for survival within different portions of the GI tract, which is in contrast to results obtained when animals are infected with only the mutant Yops. Although at first glance this appears contradictory, we think the explanation lies in our observations of changes in the GI tract during infection with wildtype Y. pseudtuberculosis. That is gastroenteritis and the inflammatory response are induced in mice co-infected with mutant and wildtype Yersinia, but not in mice infected only with the mutant strains. Therefore, we hypothesize that mutant bacteria are unable to combat the influx of immune cells into the tissues in the presence of wildtype Yersinia, but can survive in the absence of an inflammatory response.

To test this hypothesis, we have depleted mice of neutrophils and infected with a mixture of wildtype Yersinia and a yopE mutant. Preliminary data indicate that the yopE mutant survives in the small intestines and Peyer1s patches in the neutropenic mice while the yopE mutant is out competed by wildtype in the control mice in these tissues. This suggests that YopE targets neutrophils and that infection with wildtype Yersinia induces neutrophil influx.