20Huntington's disease (HD) is a progressive neurodegenerative disease that affects the striatum and 21 cerebral cortex. It is caused by a dominant CAG trinucleotide expansion in exon 1 of the HTT gene. 22Mutant huntingtin protein (mHtt) is expressed in neurons and immune cells. HD patients demonstrate 23 altered blood cytokine profiles and altered responses of peripheral immune cells to inflammatory 24 stimuli. However, the effects of mHtt on microglial immune responses are not fully understood. Herein 25 we discuss the current understanding of how mHtt alters microglial inflammatory responses. Using 26 lentivirus, we expressed the N171 N--terminal fragment of wild--type or mhtt containing 18 and 82 27 glutamine repeats in cultured EOC--20 microglial cells. We then measured responses to 28 lipopolysaccharide or interleukin--6. Mutant huntingtin--expressing microglial cells produced less 29 interleukin--6 and nitric oxide in response to lipopolysaccharide stimulation than wild--type huntingtin--30 expressing cells. However, mHtt--expressing microglia stimulated with interleukin--6 produced more nitric 31 oxide than wild--type cells. Mutant huntingtin--expressing cells had higher basal NF--κB and further 32 elevations of NF--κB after interleukin--6 but not lipopolysaccharide stimulation. Thus we demonstrate the 33 potential of mHtt to dampen responses to lipopolysaccharide but potentiate responses to interleukin--6. 34 This work adds to the emerging understanding that mHtt alters not only baseline status of cells but may 35 also result in altered immune responses dependent on the nature of the inflammatory stimuli. We also 36 present our perspective that in human HD the extent of inflammation may depend, in part, on altered 37 responses to varied inflammatory stimuli including environmental factors such as infection. 38

Toxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra--cellular parasite cysts in brain. Despite life--long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild--type and HD mice were infected at 2--months of age. During the 10--month follow--up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD--infection interaction in mice that provides insights into the large variability of the human HD phenotype.