DEVELOPMENT AND MODULATION OF IMMUNE RESPONSES TO LATENT INFECTION IN THE CENTRAL NERVOUS SYSTEM

Infection in the central nervous system (CNS) and conversion to a more quiescent state is a shared feature of many persistent pathogens. The parasite Toxoplasma gondii forms long-lived cysts predominantly in neurons, which is considered important for immune evasion. However, whether neuronal cysts fully evaded immune recognition and pressure was unclear. In these studies, mathematical modeling emphasized that cyst-directed immunity contributes to trends in cyst control typically observed in vivo. In vivo studies demonstrated evidence of cyst-directed immunity: cyst-derived model antigen induced transgenic CD8+ T cell responses in the CNS, and neuronal STAT1 signaling promoted cyst control. Further interrogation of the CD8+ T cell response to cyst antigen revealed that these responses were activated and expanded prior to CNS entry but differentiated within the brain into a phenotypically distinct memory population with reduced effector capacity. Targeted stimulation with an engineered IL-2 mutant expanded anti-cyst T cells in the CNS but did not impact cyst control. Additionally, modeling and experiments with parasites unable to form bradyzoites (Δbfd1) revealed that the absence of cyst formation in the CNS did not prevent long-term persistence but resulted in increased tachyzoite replication, CNS pathology, and mortality. These findings suggest the latent form of T. gondii is under immune pressure and that cyst conversion and anti-cyst immune restriction may represent mechanisms to promote mutually beneficial host survival.

Author dc:creator

• Eberhard, Julia, Nicole

Advisor dc:contributor.advisor

• Hunter, Christopher, A

• Immunology and Infectious Disease
• Microbiology
• Neuroscience and Neurobiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62671

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62671