We combine molecular genetics, cell biology, and biophysics to determine how a pathogen's influence on signal transduction can alter disease.

How does host-pathogen competition guide the evolution of cellular signaling?

The competition between a pathogen and its host leads to rapid evolutionary selection of mutations as each organism is locked into a never-ending evolutionary counter-attack. Typically, we study conserved genes with the notion that they are important for organism survival. In the rivalry between host and pathogen, however, polymorphic genes reveal players at the front lines. Pathogen effector molecules have evolved to block specific host signaling proteins. Such dysregulation can lead to disease by allowing a pathogen to escape clearance. The rewired signaling networks can also cause pathogenesis, as is the case with cancers. The arms race that drives the evolution of individual proteins must also shape the cell's signaling networks. The overall goal of our work is to understand how competition with pathogens has driven the evolution of cellular signaling on both sides of the host-pathogen interface.

Whereas most pathogens have a single or restricted range of hosts with which they co-evolve, the obligate intracellular parasite Toxoplasma gondii can infect virtually any cell of almost any warm-blooded animal. This is a remarkable feat – to remain a successful parasite, Toxoplasma has co-evolved with multiple diverse host species, from avians to mice and humans. Thus Toxoplasma is a superb system for the study of host-pathogen competition.

During infection, Toxoplasma secretes a large number of effector molecules into its host cell that alter diverse host processes such as cell cycle, apoptosis, and cytokine signaling. Toxoplasma strains that carry divergent alleles of these polymorphic effectors elicit radically different responses in host cells and thus cause distinct disease symptoms. One strain may kill a mouse but chronically and asymptomatically infect a bird; another second strain may do the reverse. We are working to uncover the mechanism for these differences, from the molecular and cellular to the organismal level.

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Pseudokinase function & evolution
Dysregulation of host signaling