At the PANDAS meeting last week in Irvine, my Swedish publisher, Gunilla Gerland of Pauvus Utbildning, told me about 2 new articles on Toxoplasma gondii infection, which are of interest in light of the discussion in Chap. 5 of my book of how parasites can control the behavior of their hosts: “Infections and immune activation have been implicated in childhood psychiatric disorders such as obsessive-compulsive disorder, Tourette’s syndrome, attention deficit disorder, and an autoimmune disorder caused by streptococcal [and other; PANDAS or PANS] infections. Other examples of this phenomenon include the effects of some protozoan parasites; human behavior is strikingly altered by infection of Plasmodium (malaria) and Trypanosoma (sleeping sickness). Infection in pregnant women by the protozoan Toxoplasma gondii is implicated in the development of schizophrenia in the offspring—a fascinating connection that is discussed later in this chapter.”
“The most striking evidence that T. gondii can alter behavior in the adult comes from the work of Joanne Webster at Imperial College, London. The life story of this parasite is an example of the manipulation hypothesis, wherein a parasite alters its host’s behavior for the parasite’s benefit. The only known hosts in which T. gondii can reproduce sexually are felines. The parasite mates in the cat intestine, producing oocysts (thick-walled spores) that are then shed in the feces. These spores are very stable in the environment and are highly infectious when ingested. When the oocysts are eaten by an intermediate host such as a wild rodent or a human, they undergo asexual reproduction, resulting in infection of tissues such as the heart and brain. Lest one think that there is little exposure for humans, a study of meat samples in stores in England reported that 38% contained T. gondii oocysts! Contact with spores while cleaning cat litter boxes may also be a common source of infection. These cysts can remain latent and stable in tissues for the lifetime of the host. Transmission back to the definitive cat host then occurs when a cat eats the rodent, allowing the parasite to complete its life cycle in the cat intestine. In most species studied, there appears to be little effect of the infection on the behavior of the intermediate host.”
“A striking exception is found in rats and mice, which display a form of suicidal behavior in response to T. gondii infection. Normally, wild rats are innately neophobic, meaning that they avoid novel stimuli. This is the reason they are very difficult to trap or poison. Consistent with this trait, rats display a strong aversion to areas containing cat odors. In remarkable contrast, rats infected with T. gondii not only display a reduced aversion, but actually prefer to investigate areas containing cat odors. This behavior, of course, makes it easier for the cat to kill and eat the rodent that contains the T. gondii oocysts. Thus, the parasite has manipulated the host’s behavior so as to be able to complete its life cycle by reproducing sexually in the cat’s intestine. An intriguing twist to this story is that the antipsychotic medication haloperidol, which is commonly used to treat schizophrenia, is the most potent inhibitor of T. gondii replication known. Moreover, treatment of T. gondii–infected rats with haloperidol restores their natural tendency to avoid areas containing cat odors.”
“In light of the ability of cytokines to alter behavior, as discussed in chapter 2, it is also of interest that a latent T. gondii infection can permanently alter cytokine levels in the brain of the rodent host—perhaps due to a local immune response that keeps the T. gondii dormant. T. gondii is ubiquitous in humans; 70% or more display evidence of the parasite in their brains. Though it does not seem to cause major problems for the human host, the parasite can be reactivated by immunosuppression, for example by HIV infection or chemotherapy. Thus T. gondii could play a role in psychiatric problems found in AIDS patients. There is also some recent evidence that children with high T. gondii levels display hyperactivity and low IQ. Given the widespread presence of the parasite, this is an observation that merits follow-up.”
So, the animal studies show that Toxo infection causes a suicide-like behavior in the rat. The new papers pointed about by Gunilla are epidemiologic studies in humans. These papers from Denmark and from the University of Maryland follow up on several prior papers from Turkey, Germany and the USA. The evidence is that people with elevated antibody titers against Toxo are 1.5- to 7-times more likely to commit suicide or attempt to do so, depending on the study and the elevation of the antibody titer. The correlation with the level of the antibody titer could suggest higher risk for people with more recent infections, more serious infections, or eruption of the Toxo from its quiescent phase in cysts, or that those people are hypersensitive to the parasite. More animal work on these questions is needed. It is known, however, that controlling Toxo infection requires elevated levels of inflammatory cytokines. Interestingly, suicide attemptors have elevated levels of IL-6 in the blood and cerebrospinal fluid. As discussed in the book, major depressive disorder is characterized by elevated cytokines and an inflammatory-like state. Somewhat similar findings have been made for schizophrenia and autism.
Some investigators have proposed that it is the anti-Toxo antibodies themselves that bind in the brain and change behavior of the host. There is reasonable evidence for this hypothesis in systemic lupus and paraneoplastic disorders, and this is also a major hypothesis for PANDAS, where elevated titers of anti-streptococcus antibodies are often found. Recall also the discussion in the book as to whether maternal infection stimulates the production of antibodies against the pathogen that also cross react with the brain of the fetus (molecular mimicry) and alter fetal brain development, raising the risk for autism in the offspring. A significant question in all of these cases is, however, how do such antibodies cross the blood brain barrier (BBB) and get access to the neurons and glia? Do all of these disorders also involve an acute or chronic leakiness in the BBB? Another question, which was raised at the PANDAS meeting, is if a number of very diverse pathogens such as strep (bacteria) and mycoplasma (fungi) can cause PANDAS, how do they elicit similar antibodies that can cause the similar behavioral symptoms found in PANDAS or PANS? [Note: Gunilla just sent me an old paper providing evidence of an evolutionary relationship between mycoplasma and strep, so they may generate antibodies in common after all]
In the case of Toxo, an entirely different hypothesis has arise from findings that this microbe produces a protein with the activity of tyrosine hydroxylase, the enzyme that makes the neurotransmitter dopamine. Moreover, it is known that a highly effective drug against Toxo is haloperidol, a commonly used anti-psychotic medication that blocks dopamine action. Moreover, haloperidol is able to block some of the behavioral changes seen in infected rats. Dopamine is, of course, one of the major transmitters involved in schizophrenia. Thus, if Toxo could alter dopamine levels in critical brain areas, it would represent a more direct way of modifying behavior.