Research

Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

Gretchen Hermes^1,2 , James W Ajioka³ , Krystyna A Kelly³ , Ernest Mui¹ , Fiona Roberts⁴ , Kristen Kasza⁵ , Thomas Mayr³ , Michael J Kirisits^1,2 , Robert Wollmann⁶ , David JP Ferguson⁷ , Craig W Roberts⁸ , Jong-Hee Hwang⁹ , Toria Trendler^1,2 , Richard P Kennan⁹ , Yasuhiro Suzuki¹⁰ , Catherine Reardon³ , William F Hickey¹¹ , Lieping Chen¹² and Rima McLeod^1,2,13

¹Department of Ophthalmology, University of Chicago, Chicago, IL, USA

²Committee on Immunology, University of Chicago, Chicago, IL, USA

³Department of Pathology, Cambridge University, Cambridge, UK

⁴University Department of Pathology, Western Infirmary, Glasgow, UK

⁵Department of Health Studies, The University of Chicago, Chicago, IL, USA

⁶Department of Pathology, University of Chicago, Chicago, IL, USA

⁷Nuffield Department of Pathology, Oxford University, Oxford, UK

⁸Department of Immunology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

⁹Albert Einstein College of Medicine, Bronx, NY, USA

¹⁰Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute & State University, Blacksburg, VA, USA

¹¹Department of Pathology, Dartmouth University School of Medicine, Hanover, NH, USA

¹²Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

¹³Department Pediatrics (Infectious Diseases); Committees on Molecular Medicine, Genetics, and The College, University of Chicago, Chicago, IL, USA

author email corresponding author email

Journal of Neuroinflammation 2008, 5:48doi:10.1186/1742-2094-5-48

Published:	23 October 2008

Abstract

Background

Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.

Methods

To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied.

Results

Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation.

Conclusion

In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.