Overview
Research in the Denkers lab focuses on immunity to the intracellular protozoan Toxoplasma gondii. This highly successful parasite is commonly found in humans, domestic animals, and wildlife populations. Toxoplasma stimulates a strong cell mediated immune response that normally enables host survival and establishment of long-term latent infection in the brain. It is estimated that 10-50% of the human population worldwide are infected with Toxoplasma without showing any symptoms of illness. However, the parasite can reactivate in the brain causing life-threatening disease in immunodeficient populations, and the parasite also poses a threat as a serious congenital infection. We use tools of biochemistry, molecular biology, genetics and immunology to determine how the immune system responds to infection, how the parasite evades immune-elimination, and how dysfunctional immunity can lead to host pathology and disease.
Upper left, Toxoplasma tachyzoites replicating inside an astrocyte; upper right, emergence of Ly6C+CD11b+ effector monocytes in the intestine during infection; lower left, subepithelial bacterial translocation in the intestine triggered by Toxoplasma; lower right, mobility shift assay detecting presence of activated STAT molecules in infected dendritic cells.
Initiation of Immunity
|
We are interested in determining how Toxoplasma is recognized by the innate immune system, particularly in the intestinal mucosa where infection is initiated. We are examining intestinal dendritic cell subsets and how T. gondii influences their function. We are investigating the role of Toll-like receptors in recognition and the function of MyD88-dependent signaling. New studies are examining how Wnt/beta-catenin signal transduction controls dendritic cell differentiation and emergence of immunity to Toxoplasma.
|
Immunopathology of infection
|
Infection normally results in protective immunity but sometimes leads to uncontrolled inflammatory pathology. In the brain this may result in toxoplasmic encephalitis that can be a serious problem in AIDS patients. In the intestine of some mouse strains infection causes inflammation that resembles inflammatory bowel disease in humans. We are examining the cells and cytokines that underlie this pathology, as well as determining how parasite strain controls the response.
|
Hijacking host cell
intracellular signaling |
Toxoplasma is known to directly inject host-directed kinase molecules into the cell during invasion. This results in rapid phosphorylation of members of the JAK-STAT transduction cascade that normally transmit signals from cell surface cytokine receptors to nuclear transcription factors. STAT family members activated by T. gondii include STAT1, STAT3, STAT5 and STAT6. We are examining the mechanism and consequences of Toxoplasma controlled STAT activation, particularly as related to infection of macrophages and dendritic cells that harbor the parasite in vivo. .
|