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

Department of Ophthalmology, University of Chicago, Chicago, IL, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 11/2008; 5(1):48. DOI: 10.1186/1742-2094-5-48
Source: PubMed


Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.
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 alphaPD1 ligand were studied.
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.
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.

  • Source
    • "In marked contrast to the periphery, the brain content of KYNA, 3- HK and QUIN was dramatically increased 4 weeks after infection with T. gondii, i.e. at a time when the parasite is largely controlled in the periphery (Vyas et al., 2007). This chronic phase is characterized by the presence of numerous cysts and inflammation in the brain, with activation of astrocytes and microglia (Hermes et al., 2008; Wilson and Hunter, 2004), as confirmed here by histological means. As these glial cells produce IDO and the other enzymes that are responsible for the cerebral biosynthesis of neuroactive kynurenines, and as the formation of these metabolites in the brain is known to be enhanced after immune stimulation (see Schwarcz et al., 2012 for review), it is likely that synthesis within the brain accounted for the observed changes in brain KP metabolism at this stage after infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.
    Full-text · Article · Dec 2013 · Schizophrenia Research
  • Source
    • "These can be detected easily as hyperintensities in T 2 weighted images [14] [15]. Thus, lesions in the brain with bright MRI signals have been detected and characterized successfully with respect to Shiga toxin-producing Escherichia coli infections [16], Herpes simplex encephalitis (Fig. 2) [17] [18] [19], Cryptococcal meningoencephalitis [20], Citrobacter koseri brain abscesses [21], sepsis-associated encephalopathy [22], Lymphocytic Choriomeningitis Virus infections [23], and Toxoplasma gondii brain infections [24]. Recently, endogenous T 2 contrast was also defined as early marker of cerebral malaria, one of the most severe complications caused by Plasmodium falciparum. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The investigation of microbial infections relies to a large part on animal models of infection, if host pathogen interactions or the host response are considered. Especially for the assessment of novel therapeutic agents, animal models are required. Non-invasive imaging methods to study such models have gained increasing importance over the recent years. In particular, magnetic resonance imaging (MRI) affords a variety of diagnostic options, and can be used for longitudinal studies. In this review, we introduce the most important MRI modalities that show how MRI has been used for the investigation of animal models of infection previously and how it may be applied in the future.
    Full-text · Article · Nov 2013 · Journal of pharmaceutical and biomedical analysis
  • Source
    • "For example, T. gondii persists in human pseudocysts, macrophages, and neurons. In the latent phase the parasite is in the bradyzoite stage and causes mild inflammation as a result of the host’s immune response [63]. However, dying cysts probably cause intense inflammation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review concentrates on tumours that are anatomically localised in head and neck regions. Brain cancers and head and neck cancers together account for more than 873,000 cases annually worldwide, with an increasing incidence each year. With poor survival rates at late stages, brain and head and neck cancers represent serious conditions. Carcinogenesis is a multi-step process and the role of infectious agents in this progression has not been fully identified. A major problem with such research is that the role of many infectious agents may be underestimated due to the lack of or inconsistency in experimental data obtained globally. In the case of brain cancer, no infection has been accepted as directly oncogenic, although a number of viruses and parasites are associated with the malignancy. Our analysis of the literature showed the presence of human cytomegalovirus (HCMV) in distinct types of brain tumour, namely glioblastoma multiforme (GBM) and medulloblastoma. In particular, there are reports of viral protein in up to 100% of GBM specimens. Several epidemiological studies reported associations of brain cancer and toxoplasmosis seropositivity. In head and neck cancers, there is a distinct correlation between Epstein-Barr virus (EBV) and nasopharyngeal carcinoma (NPC). Considering that almost every undifferentiated NPC is EBV-positive, virus titer levels can be measured to screen high-risk populations. In addition there is an apparent association between human papilloma virus (HPV) and head and neck squamous cell carcinoma (HNSCC); specifically, 26% of HNSCCs are positive for HPV. HPV type 16 was the most common type detected in HNSCCs (90%) and its dominance is even greater than that reported in cervical carcinoma. Although there are many studies showing an association of infectious agents with cancer, with various levels of involvement and either a direct or indirect causative effect, there is a scarcity of articles covering the role of infection in carcinogenesis of brain and head and neck cancers. We review recent studies on the infectious origin of these cancers and present our current understanding of carcinogenic mechanisms, thereby providing possible novel approaches to cancer treatment.
    Full-text · Article · Feb 2013 · Infectious Agents and Cancer
Show more