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Immune Response to Developmentally-Dependent Expression of Toxoplasma gondii Antigens

  • Author(s): Worth, Danielle
  • Advisor(s): Wilson, Emma H
  • et al.
Abstract

The switch from tachyzoite to bradyzoite enables the protozoan parasite, Toxoplasma gondii to establish latency in its host, and the immune response to the cyst stage of the parasite remains largely unknown. The work presented in this dissertation aim to establish the immune response to bradyzoite and cyst wall antigens.

Macrophages are critical for controlling cyst burden, yet the receptors involved are unknown. I investigated the PRR, dectin1, in macrophage-cyst recognition, due to its role in macrophage responses to chitin in vitro, and fungal pathogens in vivo. We find that dectin1 is not required to control parasite burden or induce an inflammatory response in vivo. Contrary to our hypothesis, dectin1-/- mice display no differences in cyst numbers in the brain, but rather, dectin1 plays an indirect role by regulating inflammation.

The immune system contributes to the parasites developmental switch in vivo, but parasite-specific factors are unclear. AP2 transcription factors contribute to developmental switching in other apicomplexans, and here, we examined AP2IV- 4 during Toxoplasma infection to determine if misexpression of bradyzoite antigens influences infection and cyst formation. We find that ΔAP2IV-4 parasites do not encyst in the brain. High dose infection with wild-type parasites results in 100% mortality by day 6 post-infection, whereas the PruΔAP2IV-4 mice survive. The response to PruΔAP2IV-4 is driven by inflammatory monocytes, which are known for their ability to control parasite replication.

Despite the progress in the field, we know little about the growth and development of Toxoplasma cysts, and the cues for bradyzoite differentiation. Studying this in vivo is difficult, and studies have used artificial means to generate cysts. Thus, we need a system for studying this in vitro, that will facilitate our understanding of cyst development and host-parasite interactions. Here, I validate that cysts form spontaneously within neurons in vitro and neurons actively respond to parasite infection, but are poor antigen presenting cells.

In this dissertation, I demonstrate that expression of stage-specific antigens shape the outcome of the immune response. Understanding this developmental switch in vitro and in vivo will reveal novel vaccination strategies or treatments targeted to latent stages of infection.

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