Sibley Lab Research
We are interested in survival adaptations of intracellular parasites that are important pathogens in humans. We study Toxoplasma, a protozoan parasite that infects virtually all types of nucleated vertebrate cells and which provides a model for studying host cell invasion by apicomplexan parasites, a group that also includes malaria and Cryptosporidium. Our studies have shown that Toxoplasma actively penetrates its host cell using a novel process that depends on the parasite’s actin cytoskeleton. We are examining the regulation of actin-based motility, which is an essential and unique aspect of the biology of this group of parasites.
Within the host cell, the parasite resides within a specially modified vacuole that is derived from the plasma membrane during invasion, but remains segregated from other endocytic compartments and fails to undergo normal processing. The parasite containing vacuole is extensively modified by secretion of proteins and lipids from the parasite. Our recent studies have shown that parasite secretory kinases are released into the host cell during invasion and that they modulate host cell signaling and mediate intracellular survival. These adaptations allow the parasite to escape innate immune mechanisms that are designed to clear intracellular pathogens.
One important approach for understanding the molecular basis of intracellular parasitism is the development of molecular and genetic techniques to complement cellular and biochemical studies. We are involved in the development of genetic tools for Toxoplasma including forward genetic mapping of virulence determinants, development of vectors for DNA transformation and protein expression, and large-scale sequencing for gene discovery and comparative genomics. These approaches are being applied to identify the molecular basis of virulence and to examine mutants with altered phenotypes in adhesion, invasion, and intracellular survival. We are also examining the population structure of Toxoplasma to determine how adaptations for enhanced transmission between hosts have shaped the evolution of this important human pathogen.