UC Riverside

Toxoplasma gondii (T. gondii) is one of the most prolific parasites in the world where it is estimated that 30% of the human population is infected. The encystment of the parasite in CNS-neurons results in a lifelong chronic infection. Within the brain, a pro-inflammatory response is essential to prevent parasite reactivation, however, an anti-inflammatory response is also required to prevent inflammation-induced mortality. This suggests a balanced immune response to the pathogen. Infection in the immunocompetent experience asymptomatic infection, further suggesting a tightly regulated immune response in the CNS. However, it is unclear what are the signals or cell-mediators that regulate this delicately balanced immune response. In addition, parasite recrudescence leads to lethal toxoplasmic encephalitis if left untreated in immunocompromised individuals. However, it is unclear what developmental pathways the parasite undergoes upon reawakening from its dormant state. This dissertation investigates these unknowns in the follow ways:

Chapter 1 is an introduction to T. gondii infection and the effects the parasite has on the host. Topics covered in this section include the life cycle and the immune response to T. gondii. This encompasses evasion strategies by the parasite, and signals that are required for protective immune cells to traverse the blood brain barrier. This chapter ends on describing the role astrocytes play in the CNS, and the implications of T. gondii infection on glutamate regulation.

Chapter 2 describes the attempts that have been made to study recrudescence of tissue cysts. This chapter poses a new ex vivo model of bradyzoite-initiated development that better preserves the key attributes of the parasite’s intermediate life cycle. In chapter 3, we discuss elements found in the CNS-microenvironment during chronic T. gondii infection, and consider how tissue-derived signals, such as high extracellular glutamate, influence protective CD8 T cells. Chapter 4 investigates if a potential mechanism for the cause of GLT-1 downregulation in astrocyte is due to direct invasion.

Finally, chapter 5 reviews topics discussed in previous sections, and highlights my contributions to the fields of neuroimmunology and parasitology. Furthermore, this chapter emphasizes work that still needs to be done and unanswered questions in the field.