Toxoplasma Strain-specific Early Immune Responses Determines Sub-acute CNS Immune Responses
AdvisorKoshy, Anita A.
Goodrum, Felicia D.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractToxoplasma gondii is an obligate intracellular parasite that infects up to 1/3 of the world’s population. Genetically distinct Toxoplasma strains show differences in acute and chronic virulence in mice, and possibly in humans. In determining the mechanisms that cause these differences, recent in vivo data have revealed that Toxoplasma polymorphic effector proteins can modulate different innate immune responses in a strain-specific manner. But little is known about how these differences play out in the central nervous system (CNS), the major organ affected in human disease. To address this gap, we infected mice with two canonical Toxoplasma strains (type II and type III) and examined the systemic and CNS immune responses. We observed that at 5 days post infection (dpi), type III-infected mice polarized macrophages to alternatively activated (M2) phenotype, whereas, type II-infected mice had more classically activated (M1) phenotype in the spleen. At 21 dpi, we found that despite having similar parasite burden, the CNS of type III-infected mice had a more pro-inflammatory CNS immune response (macrophages and T-cell response, and cytokines/chemokines) and a significantly lower M2s and regulatory T cells as compared to type II-infected mice. Taking these data together, we propose that early immune responses determines the later sub-acute CNS immune response during Toxoplasma infection. To test this idea, we engineered a type III strain that lacks ROP16, the polymorphic effector protein that drives the early M2 response. Type IIIΔROP16-infected mice showed a more type II-like CNS response with lower levels of infiltrating T cells and macrophages/microglia and higher numbers of M2s as compared to type III strain. Collectively these studies suggest that early immune response differences play a key role in determining the later sub-acute immune response.
Degree ProgramGraduate College