Although adaptive, cell-mediated immunity has long been known to be critical for controlling T. gondii infection, it is now appreciated that innate immune recognition and effector functions also play an important role in host defense against the parasite. We are working to identify host cell pathways that contribute to early recognition of T. gondii by human peripheral blood monocytes and to define the parasite factors involved in these processes. (At right, an intracellular rosette of T. gondii in a human monocyte)
2. Dissemination in the host: how does T. gondii cross biological barriers?
A remarkable feature of T. gondii infection is the ability of the parasite to disseminate broadly in the infected host and to enter a diverse range of tissues, including the brain, heart, eye, and placenta. What remain unknown are the molecular mechanisms that mediate the transmigration of T. gondii out of the bloodstream and into tissues. We are developing human cell approaches using microfluidic technology to examine parasite interactions with vascular endothelium in conditions of shear stress and in vivo intravital imaging strategies to address these questions.
Infected and uninfected human monocytes flowing over endothelial cells in conditions of physiologic shear stress
3D reconstruction of integrin distribution on uninfected (left) and infected (right) monocytes
3. T. gondii modulation of the surface proteome
Macrophages and dendritic cells serve as sentinels of host defense, by initiating microbicidal activities and alerting other cells of the immune system to the presence of an infection. As a highly successful pathogen, T. gondii has evolved the ability to evade, modulate, or manipulate the activities of these cells in order to persist. We are particularly interested in how the parasite alters the expression of immune receptors and ligands on the surface of infected cells, thereby altering communication between infected cells and other cells in the environment. We are combining genomics and proteomics approaches to characterize the surface of infected and uninfected cells and investigating the functional consequences of altered immune receptor expression. (Below, heat map and volcano plot displaying microarray data from primary macrophages)
