In the Jensen laboratory, we study the immunology and pathogenesis of the obligate intracellular parasite Toxoplasma gondii, the causative agent of human toxoplasmosis. Toxoplasma has been dubbed the “ubiquitous” parasite because it infects all species of mammals, a variety of birds and a third of the human population. How this wide spread parasite is able to achieve parasitism and yet maintain host survival across such a wide host range is the subject of ongoing investigation. We use genetic, molecular and immunological approaches to identify parasitic virulence factors that modulate a range of immunologically based phenotypes. These phenotypes include intestinal inflammation, macrophage function, T cell stimulation and the ability of Toxoplasma to evade immunological memory responses. The diverse host range that Toxoplasma encounters has generated polymorphic parasite virulence factors tailored to manipulate the immune systems of various species around the globe. By studying these virulence factors, what they target and how they work, we believe novel aspects about the host immune system can be learned.

Fueling our work is the fact that parasitic diseases are a major public health problem in the developing and third worlds and progress in developing treatments has been slow. For example, nearly half (~45%) of all childhood deaths related to infection are due to eukaryotic pathogens and yet to date (2016) there is only one partially protective vaccine in use for any human parasitic disease (the Malaria RTS,S vaccine with 27% efficacy). Thus, we are using Toxoplasma as a model to understand requirements for host immunity to eukaryotic pathogens. Due in part to the life-cycle complexity of most parasites, it is difficult to achieve immunity using current vaccination protocols, which almost exclusively work through the generation of neutralizing antibodies. However, not all pathogens can be restricted in this way alone. Instead control of many parasites like Toxoplasma require the additional help of cytotoxic T cells, which are tightly regulated and can be “turned off” during sustained periods of infection. Using host genetic screens and immunological assays we are identifying ways to optimize T cell mediated memory responses against highly virulent strains of Toxoplasma.

The murine model of toxoplasmosis also provides us with one of the few experimental systems to investigate intestinal inflammation of the small bowel (as opposed to large intestine). Toxoplasma is an orally acquired pathogen and infection occurs when one consumes undercooked meat harboring tissue cysts or food contaminated with oocysts shed in the feces by an infected cat- the definitive host. Subsequently, many animals develop severe necrosis of the small intestine that mimics the human inflammatory bowel disease, Crohn’s. We are interested in determining why certain strains of mice develop small intestinal inflammation while others do not. Identifying host susceptibility genes may open up possibilities for therapeutic intervention of inflammatory bowel diseases, like Crohn’s.

Toxoplasma is therefore a fantastic model parasite to study host-pathogen interactions. We hope results generated in our lab will have far reaching implications for the treatment of human parasitic diseases, and improve our understanding of basic immunological processes. Contact the Jensen lab if you are interested in what we do.

Questions

1) How does Toxoplasma regulate adaptive immunity?

2) Can we reinvigorate the adaptive immune response to poorly controlled parasitic infections?

3) What are the host genes that influence susceptibility to Toxoplasma infection?

4) What are the mechanisms by which Toxoplasma co-opts the host-cell to “turn off” small intestinal inflammation?