Why are some pathogens more virulent than others? Why are some host’s more susceptible to infection than others? Why do you always seem to get the cold and your friend doesn’t? These types of questions are commonly asked in the field of host-pathogen interactions. Different disease outcomes can be clearly demonstrated in the Toxoplasma model of oral infection. Following oral infection with Toxoplasma, certain strains of mice are susceptible to infection and develop severe ileitis (C57BL/6 or “B6” mice) while other mice of different genetic backgrounds (AJ mice) are resistant and fail to develop disease. Furthermore, certain Toxoplasma strains cause robust intestinal inflammation (type II) while other parasite strains (type III) do not. Therefore, the genetics of the host and parasite determine disease outcome, a model that mimics many aspects of the human inflammatory bowel disease, Crohn’s.
The virulence factor ROP16, a Toxoplasma kinase that is injected into the host cell and activates the JAK-STAT3/5/6 pathways, makes the host able to control parasite infection which in turn lessens intestinal inflammation following oral infection. However, the mechanism by which this is achieved is still not clear. We are interested in determining how ROP16 works to assist immune defense mechanisms against Toxoplasma.
On the host side, using gene expression QTL (eQTL) analysis a candidate gene was identified that may explain host susceptibility to oral infection and intestinal inflammation. We are currently investigating the role of this gene in murine toxoplasmosis.
Shown above: The small intestines from mice orally infected with Toxoplasma were monitored for infection and relative parasite numbers are depicted as a heat map. The parasite strains used in this experiment were engineered to express the luciferase gene and hence, parasites can be detected in tissues by single photon emission using a sensitive super-cooled camera in an IVIS machine. The B6 mouse has 300 fold more parasites in the small intestine compared to the AJ mouse, and histology sections below show extreme villus blunting and necrosis in the B6 mouse but relatively normal looking villi in the AJ mouse. The Toxoplasma type II and III strains differ radically in how they cause infection, and as such “Toxoplasma cannot balance in every host”. Balancing is a central problem for Toxoplasma as it is “ubiquitous” and can infect most warm blooded vertebrates. Different strains have likely adapted to different hosts, and these adaptations are reflected in an array of polymorphic virulence factors, many of which intersect immune pathways. A central premises in the lab is that by studying virulence factors we might learn novel aspects about the immune system.