Once it enters the body, T. gondii
traverses the intestinal or placental epithelium as a free parasite by paracellular transmigration1
and enters circulating cells such as macrophages2,3
or dendritic cells.3,4
It then appears to use such cells as a “Trojan horse” to gain access to privileged sites such as the brain.
In vitro studies using mouse brain cells have demonstrated that tachyzoites invade microglia,5,6
and the parasite thereafter forms cysts within these cells.6,8
An in vitro study using human neurons and astrocytes showed that T. gondii
also forms cysts in these cells.10
Human cell division autoantigen-1 was recently identified as a key host determinant of bradyzoite development within human fibroblasts.11
Electron microscopy studies on brains of chronically infected mice demonstrated that the majority of cysts are in neurons12,13
; the cysts were identified within axons, dendrites, or the cell body of the neurons.13
In mice with congenital toxoplasmosis, cysts were also found within neurons in their brains.14
In humans, proliferating tachyzoites have been detected in glial cells in a patient who had developed toxoplasmic encephalitis.15
In another case of toxoplasmic encephalitis, T. gondii
bradyzoites were observed in a Purkinje cell in the cerebellum.16 Toxoplasma gondii
cysts have also been reported in astrocytes in humans17
; in that study, astrocytes were the only cell type that could be identified due to the poor preservation of the samples. Collectively, these studies demonstrate that T. gondii
can infect a variety of brain cells, but additional studies are needed to identify the host cells that preferentially harbor cysts within the brain.
The effects of T. gondii
on brain cells can be almost immediate, as shown by the work of Blader et al,18
who used tachyzoites of a type II strain to examine host gene expression profiles in infected human fibroblasts. Within the first 2 hours of infection, although <1% of the 22 000 known human genes examined were upregulated by >2-fold, almost half of the affected genes encoded proteins associated with the immune response. Included among the upregulated genes were those encoding chemokines (GRO1, GRO2, LIF, and MCP1) designed to recruit immune cells, cytokines (IL-1β and IL-6) capable of activating immune responses, and transcription factors (REL-B, NF-κBp105, and I-κBα) that can promote expression of additional immune regulators. Thus, it is clear that the host cell mounts a strong response directed at alerting and activating the immune system to react to the infection.
Twenty-four hours postinfection, by which time the parasite has replicated 2–4 times, a variety of host glycolytic and mevalonate metabolic transcripts are upregulated, presumably, in response to the nutritional drain imparted by the infection. Intracellular tachyzoites are also known to manipulate a variety of signal transduction pathways related to apoptosis,19–21
antimicrobial effector mechanisms,22–25
and immune cell maturation.26
The recent finding of delivery of protein phosphatase 2C released from rhoptries of tachyzoites into the host nucleus27
will likely be a key step forward toward understanding the molecular basis of such transcriptional manipulation. Although similar studies on brain cells have not been reported, it seems likely that T. gondii
infection may also influence signaling pathways in the brain.
There is only limited information on manipulation of host cells by bradyzoites. Foudts and Boothroyd28
recently reported that many of the same host genes (eg, cytokines and chemokines) are affected by infection with bradyzoites or tachyzoites in human fibroblasts; however, the number of genes and the magnitude of activation were both lower in bradyzoite infection. Future gene expression studies on tachyzoite and bradyzoite infection of brain cells may reveal cell type–specific changes influencing the secretion of not only cytokines and chemokines but also neurotransmitters, receptors, ion channels, and other central components of brain physiology.
Elevated anti-T. gondii
IgG antibody levels have been reported in patients with first-onset schizophrenia,29,30
suggesting an involvement of this parasite in the etiology of schizophrenia. Elevated serum levels of IL-1β have also been detected in individuals with acute schizophrenia, but not chronic schizophrenia,31
and there were no differences in IL-1β or IL-6 serum or cerebro-spinal fluid levels in medicated patients compared with a control group.32
Because tachyzoites induce more pronounced inflammatory cytokine responses in host cells than do bradyzoites, as described above, proliferation of tachyzoites in the brain may be related to the onset of schizophrenia. The lack of elevated IL-1β or IL-6 in medicated patients could be due to the antitoxoplasmic activity of some antipsychotic drugs.33,34
Interestingly, anti-T. gondii
IgM antibody, a key indicator of acute acquired infection, is not elevated in the sera of patients with first-onset schizophrenia,29,30
implying that the patients are not in the acute stage of a newly acquired infection. Therefore, a reactivation of chronic infection with the parasite (proliferation of tachyzoites caused by cyst rupture) in the brain might be involved in the onset of the disease. In support of this possibility, expression levels of proinflammatory cytokines, including IL-1β and IL-6, are higher in the brains of a mouse strain in which tachyzoite proliferation occurs in this organ during the later stage of infection compared with the brains of another mouse strain that prevents tachyzoite proliferation during chronic infection.35
It is noteworthy that individuals with congenital T. gondii
infection often develop ocular toxoplasmosis later in life,36
and the disease is considered to be due to reactivation of infection. The onset of toxoplasmic chorioretinitis is most frequent during the ages of 20–30,36
correlating well with the age of onset of schizophrenia.37
Therefore, congenital infection with T. gondii
may be involved in the etiology of schizophrenia.