Cerebral Toxoplasmosis. Pathogenesis, Host Resistance and Behavioural Consequences.

Following infection with Toxoplasma gondii, tachyzoites proliferate within a variety of nucleated cells in various organs during the acute stage of infection. Interferon-gamma (IFNγ)-dependent cell-mediated immune responses, and humoral immune responses to a lesser extent, control the tachyzoite proliferation, but the parasite establishes a chronic infection by forming tissue cysts, especially in the brain, heart and skeletal muscle. IFNγ can activate microglia, astrocytes, and brain microvascular endothelial cells to prevent tachyzoite growth by using different mechanisms depending on the cell types. T cells are an essential producer of IFNγ to control tachyzoites, and interleukin (IL)-12 plays a crucial role in inducing their IFNγ production. Many other cytokines such as TNF-α and IL-6 are involved in the IFNγ-mediated protective immune responses against tachyzoites in the brain. In addition, multiple cytokines and molecules such as IL-10, IL-27, and lipoxin A4 play important downregulatory roles on the immune responses to prevent development of immunopathology. T. gondii can form cysts in multiple cell types in the brain, including neurons and astrocytes. Recently, CD8⁺ T cells were revealed to have an activity to remove tissue cysts from the brains of chronically infected mice. This anti-cyst activity of the T cells is does not require their IFNγ but requires perforin. Therefore, the immune system appears to use two different mechanisms, one is mediated by IFNγ and another is mediated by perforin, depending on the stage of the parasite that it targets. Therefore, cerebral infection with T. gondii is controlled by well-organized and orchestrated functions of the immune system. Genetic factors in both the host and the parasite also affect the susceptibility to the cerebral infection. Although chronic infection with T. gondii has been considered as "latent", recent studies indicated a correlation of the infection with cryptogenic epilepsy and neuropsychiatric disorders such as schizophrenia. T. gondii can also cause congenital infection to the fetus, in which the brain is the major organ affected.