Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early-advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.
Department of Veterinary Sciences, University of Wyoming, Laramie, WY, United States of America.|Neuroscience Graduate Program, University of Wyoming, Laramie, WY, United States of America.
David W
DW
Donley
Department of Psychology, University of Wyoming, Laramie, WY, United States of America.
Andrew R
AR
Olson
Department of Veterinary Sciences, University of Wyoming, Laramie, WY, United States of America.
Merl F
MF
Raisbeck
Department of Veterinary Sciences, University of Wyoming, Laramie, WY, United States of America.|Neuroscience Graduate Program, University of Wyoming, Laramie, WY, United States of America.
Jonathan H
JH
Fox
Department of Molecular Biology, University of Wyoming, Laramie, WY, 82071, United States of America.
Jason P
JP
Gigley
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006816:Huntington Disease / Q000150:complications* / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D061213:Mortality, Premature; D059208:Parasite Load; D010641:Phenotype; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000150:complications* / Q000469:parasitology
D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine