Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

Abstract

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.

LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

“…WT and YAC128 HD mice (Jackson Labs) were maintained as described [41]. Mice were housed in OptiMice cages (Animal Care Systems) with 4--5 per cage and one genotype/treatment per cage [39]. Experimental mice were obtained by breeding mutant HTT males with WT females.…”

“…Assessment of antigen--specific IFNγ production from CD8+ T cells was performed as described [39]. Flow cytometry data were collected using Guava easyCyte HT flow cytometer (Millipore).…”

“…Amplifications used a Bio--Rad CFX real--time thermal cycler. T. gondii burden was determined by quantitative PCR on genomic DNA using DNA standards as described [39]. Reactions were carried out with 400 ng of genomic DNA purified brain homogenate using a Qiagen DNeasy Kit.…”

“…Interestingly, a transgenic mouse model of Alzheimer's disease has an enhanced inflammatory response to acute T. gondii infection [38]. We have previously studied T. gondii infection in N171--82Q HD mice and reported premature mortality compared to non--infected HD mice [39]. However, on the B6/C3H genetic background of these mice, latent infection was not established, and the mice died before effects on HD could be investigated.…”

Neurophysiological Changes Induced by Chronic <em>Toxoplasma gondii</em> Infection

“…Elevated kynurenic acid is also observed in the brains of schizophrenia and bipolar sufferers [36,37]. Chronic T. gondii infection induced early activation of tryptophan metabolism and kynurenic acid production in a Huntington's disease mouse model [13]. A seven-fold increase in kynurenic acid was observed in the brain of infected animals [38].…”