Eukaryotic Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Signal Transduction; Vision science
Toxoplasma gondii is an obligate intracellular parasite that has the unique ability of infecting most nucleated cells in almost all warm-blooded animals. It is one of the most widespread infections in the world: approximately 50 percent of the world‘s population is infected. Luckily, most infected people are asymptomatic; however, in AIDS patients and other immune-compromised individuals, Toxoplasma causes serious and life-threatening disease. Besides its own medical importance, we study Toxoplasma because it represents an ideal model system to study how other related pathogens cause disease. These include Plasmodium, which is the causative agent of malaria that is responsible for millions of deaths worldwide, and Cryptosporidium, which causes another important secondary infection in AIDS patients. Toxoplasma is a great model system because it can easily be grown in vitro, its genome has been sequenced and it can be genetically manipulated.
My research team and I are focused on two different but related questions. First, we want to know how the parasite grows inside of its host cell. One of the important things Toxoplasma must do to grow is hijack host cell pathway and factors. We are using functional genomic assays such as microarrays and genome-wide RNA interference (RNAi) screens to identify these host factors. Identifying them is important because if the parasite cannot use these pathways, the parasite will not grow or cause disease. Thus, these pathways represent novel drug targets. As an example, we discovered that oxygen-regulated transcription factors in the host cell are necessary to support parasite growth. We are currently identifying how these transcription factors function and how the parasite adapts to the various oxygen environments it encounters during its lifecycle.
Second, we want to know how Toxoplasma affects the central nervous system and how anti-Toxoplasma immune responses function in the central nervous system. These questions are important because Toxoplasma primarily causes disease in the brain and retina. Our work has revealed that when Toxoplasma actively grows in the brain (a condition known as toxoplasmic encephalitis), it causes a massive reorganization of inhibitory synapses. These changes inhibit GABAergic synaptic transmission and this inhibition is a major factor in the onset of seizures in infected individuals. A second line of research using an ocular infection model has focused on defining how immune responses in the central nervous system are generated by Toxoplasma and then resolved once the infection is under control.