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  • Book
    Anjali Joshi Shastri.
    The ubiquitous parasite Toxoplasma gondii has developed an exquisite arsenal of effectors to support its intracellular lifestyle and its persistence within its diverse hosts. In order to survive and resist clearance, this obligate intracellular parasite must contend with the host immune response. Different strains of the parasite vary dramatically in their interaction with the immune system, and studying these strain differences has furthered our understanding of the spectrum of host-pathogen interactions and led to the identification of parasite effectors. The work described here dissects the interactions between different strains of the parasite and host macrophages: innate immune cells that paradoxically both serve as a niche for parasite replication and defend the host against parasite infection. Chapter 1 introduces Toxoplasma, the immune response to infection, and discusses the role of known parasite effectors. Experiments described in Chapter 2 identify a novel secreted parasite factor, GRA25, which modulates cytokine secretion in macrophages and controls parasite virulence in mice. In Chapter 3, high throughput methods are used to characterize the transcriptional and phosphorylation landscape of macrophages infected with different Toxoplasma strains. These analyses demonstrate that a secreted polymorphic tyrosine kinase, ROP16, directs murine macrophage polarization towards an alternatively activated phenotype. They also reveal that Toxoplasma parasites activate the Type I interferon response, a response classically associated with cytosolic pathogens. Chapter 4 describes work demonstrating that Toxoplasma strain-specifically modulates the innate immune response via secretion of a parasite factor, MAF1, which recruits host mitochondria to the parasitophorous vacuole. Finally, Chapter 5 discusses the future directions and implications of this work in the broader context of host-pathogen interactions.
    Digital Access   2013