Lindsey A Shallberg (Mentor: Christopher Hunter, PhD)
“Immune responses to latent infection in the central nervous system”
Lindsey A. Shallberg, Christopher Giuliano, Chandrasekaran Sambamurthy, Emily F. Merritt, Julia Eberhard, Anita A. Koshy, Sebastian Lourido and Christopher A. Hunter
The latent life cycle of pathogens is canonically thought to (1) allow for persistence, (2) subvert immune responses, and in some pathogens (3) is necessary for transmission to the next host. The parasite Toxoplasma gondii forms its latent life stage, the bradyzoite or cyst, in neurons in the central nervous system (CNS). Current dogma holds that because this stage is in neurons it evades immune surveillance and ensures chronicity. However, cyst numbers decline over time in mice and man, indicating there may be anti-cyst immune responses. Utilizing a neuronal specific Cre revealed that neurons respond to cytokines through STAT1 signaling during infection, and mice lacking STAT1 in neurons had more and larger cysts in the CNS following T. gondii infection. Additionally, infection with transgenic parasites in which OVA expression was restricted to the bradyzoite life stage resulted in priming of OT-I during chronic infection, indicating that adaptive immune responses can be mounted against the latent parasite life cycle. These instances of anti-cyst immune responses led us to compare immune responses to the fast-replicating tachyzoite versus bradyzoite in the CNS through generation of ΔBFD-1 parasites, which do not switch to the latent bradyzoite life stage. Although the immune response was intact, infection of mice with ΔBFD-1 parasites led to uncontrolled parasite replication in the CNS during chronic infection, with high levels of brain necrosis and lethality. In mice that survive ΔBFD-1 parasite infection, parasites were found to persist as long as 6 months in the CNS in the absence of cyst formation. Together, these data suggest a host-protective role for the formation of the cyst and alter our long-held assumptions on the latent pathogen life cycle.