A behavioral model for Toxoplasmosis gondii infection
Bing Mei Wang
D. Scott Smith, MD
Human Biology 153
26 February 201
Toxoplasma gondii is one of the most ubiquitous blood-and-tissue dwelling protozoa in the world (Markell & Voge). It belongs to the phylum Apicomplexa, and demonstrates the classic sporozoan alternation of schizonic (asexual) and sporogonic (sexual) cycles in its intermediate and definitive hosts, respectively. While its definitive hosts are certain members of the Felidae family, it is believed to infect all warm-blooded animals, both birds and mammals, during the asexual stage of its reproductive cycle (Tenter et al. 2000).
Toxoplasmosis has been observed in humans since at least the late 19th century; however, it was recognized only as recently as 1960 as a coccidian upon discovery of the intestinal stage of sexual reproduction in the small intestine of cats. While the majority of human infections are asymptomatic, the preference of tissue cysts for the central nervous system can cause a number of threatening complications in infants and persons who are immunocompromised. More interestingly, there have been several case studies of mental disorders caused by toxoplasmosis – most notably schizophrenia. Since T. gondii has a remarkably cosmopolitan distribution, and in some endemic areas can affect 100% of the population, the neuropsychiatric effects of toxoplasmosis have unique public health implications.
My research will thus focus on the biochemical and evolutionary mechanisms of neural pathology caused by T. gondii. I will first elucidate important elements of the Toxoplasma life cycle. I will then discuss “manipulation theory” and the modification of host behavior to increase the likelihood of sexual reproduction, especially as it pertains to the predation of mice and rats by felines. I will finally discuss psychological and clinical implications of T. gondii infection in humans, compare and contrast the mechanisms for behavior modification in these hosts, and ultimately argue that the behavioral modification abilities of Toxoplasma does not hold in humans as it does for rodents.
The life cycle of T. gondii affords many opportunities for transmission. In the intermediate host, T. gondii undergoes two stages of development. In stage one, tachyzoites multiply in many types of host cells by endodyogeny. In stage two, tachyzoites initiate the formation of tissue cysts, which are characterized by the slow endodyogeny of bradzoites. Endodyogeny is a form of asexual reproduction that involves the development of two daughter cells within a mother cell, which is consumed by the offspring upon their maturation. These cysts are found predominately in the central nervous system. Ingestion of cysts by the definitive host leads to a stage of endodyogeny. This is immediately followed by a stage of repeated endopolygeny, which occurs when several organisms are produced at once via internal budding, in small intestine epithelial cells. The final stage bradyzoites reproduce sexually to form unsporulated oocysts, which are then expelled in the feces of the definitive host. Sporulation occurs in the external environment, leading to infectious oocysts. Each oocyst contains two sporocysts, which each contain four sporozoites.
Figure 1. Life Cycle of Toxoplasma gondii (Tenter et al. 2000)
Figure 2: Modes of Transmission (Tenter et al. 2000)
Within this life cycle, T. gondii experiences three infectious stages. Infection can take place through horizontal transmission in two ways; 1) oral ingestion of infectious oocysts or 2) oral ingestion of tissue cysts. The third type of transmission can occur vertically through passing on of tachyzoites trannsplacentally. Thus, transmission of T. gondii can occur between intermediate hosts, between definitive hosts, from intermediate to definitive host, and from definitive to intermediate host (Tenter et al. and Markell & Voge). The multifarious ways in which T. gondii can infect both its definitive and intermediate hosts may partially account for its cosmopolitan success.
T. gondii in cats and rats
The ability of T. gondii to alter behavior of the intermediate host has been hotly debated for some time. Parasitic alteration of host behavior is best described in Thomas et al. as the expending of energy by the parasite to interact, either indirectly or directly, with the central nervous system of its host, as an adaptive result of selective pressure. This definition has several implications. Foremost, the alteration would lead to behavior that confers a significant advantage to the parasite, usually to increase the rate of its transmission. Furthermore, the resulting effect on host behavior would be highly specific; fewer physiological and biochemical changes mean less opportunity for the host’s immune system mount a response. Finally, the specificity of this response is a “sophisticated product of parasite evolution” (Berdoy et al. 2000) made possible by the rapidity of protozoan replication in both intermediate and definitive hosts, and not an accidental side-effect of infetion.
In line with this theory, T. gondii has long been suspected of being capable of altering host behavior. While it is capable of infecting a plethora of intermediate hosts species, it must eventually reproduce sexually in the cat. This mode of sequential parasitism introduces an exciting potential for host manipulation. For this reason, researchers began by observing behavioral changes in infected mouse models. Their hypothesis was that Toxoplasma tachyzoites and bradyzoites, which overwhelmingly prefer to encyst in the tissues of the central nervous system, are in a uniquely privileged position to manipulate behavior in the host. Furthermore, wild rats (Rattus norvegicus) represent a large and persistent intermediate host reservoir for Toxoplasma – some studies have documented the prevalence rate at 35% across all populations (Webster et al. 1994). Since R. norvegicus are common prey for many Felidae, there is likely strong selective pressure for behaviors that override millennia of evolved fear of cats, thus increasing the likelihood that an infected rat will be ingested and Toxoplasma able to sexually reproduce in its definitive host.
Earlier studies demonstrated increased activity and decreased fear of novelty (neophobia) in infected murine models. Both of these behavioral shifts could place wild rats at higher risk for predation. However, they were unable to determine that these behaviors were not associated with overall host health. Indeed, Hrdą et al. noted the “transience” of behavioral changes in mice, by tracking the behavior of infected mice over time. Using the hot-plate test to monitor escaping behavior, the open-field test to monitor exploratory behavior, and the tail-flick test to monitor antinociception, they demonstrated no significant difference between uninfected mice and infected mice past the initial stages of pathogenesis (2000). There was thus conflicting evidence for the behavioral modification theory of Toxoplasma parasitism.
However, a new wave of research beginning with Berdoy et al. provides a more adequate explanation for the behavioral effect on mice due to Toxoplasma. An experiment conducted in 2000 demonstrated that infected wild rats were attracted, rather than repelled by, the odor of cat urine. Furthermore, the altered behavior of these rats was limited to cat odor; both uninfected and infected rats behaved similarly when presented with their own odor or the odor of rabbits (a mammalian non-predator). The findings of Berdoy were confirmed in a two-part study conducted by Vyas et al. at Stanford University in 2007. The first part of the study demonstrated that behavioral changes caused by toxoplasmosis in rodents are extremely specific with respect to cat odors. In comparing control rats to infected rats, this study confirmed the following. First, control rats have a natural, innate aversion to bobcat urine as opposed to rabbit urine. This aversion is hard-wired, and can be found even in laboratory-raised rodents with no previous exposure to cats. Second, the disappearance of fear in infected rats is highly specific, as it does not disrupt many other fear-related behaviors e.g. anxiety in an open-field arena, fear conditioning via electroshock, or neophobia toward new food scents. Indeed, infected rats experienced actual attraction to cat kairomones (pheromones found in cat urine), while maintaining an aversion to dog urine. Third, infection did not affect spatial learning (think cheese and mazes). Finally, infection did not inhibit the social transmission of food preferences. These results demonstrate that infection with T. gondii overcomes both innate and adaptive fear-responses only to cat urine, providing substantial support for the behavioral modification theory of parasitism. Moreover, bioluminescence of infected rats revealed that bradyzoid cysts were located significantly in the medial and basolateral amygdalar structures, widely known to be active in the innate, olfactory fear response. These cysts were found in frequencies twice that of nonamygdalar structures previously shown to be both responsive (e.g. olfactory bulbs, the ventral hippocampus, the prefrontal cortex, and the hypothalamus) and nonresponsive (e.g. dorsal hippocampus) to kairomones.
The first study conducted by the Stanford group elucidated the mechanism by which Toxoplasma overcomes the innate fear response to cat pheromones. The second study demonstrated that Toxoplasma also affects learned fear responses as well. The researchers hypothesized that the modification of rodent behavior due to T. gondii would follow a non-monotonous function; when there were low levels of kairomones, it would be unnecessary for the parasites to carry out behavior altering biochemistry. Furthermore, when there were extremely high levels of cat pheromones, the energy expended by the parasite to overcome the immense innate response would not be cost-beneficial. Thus, the researchers proved that Toxoplasma infection conditions a cat response based on the strength of pheromone stimulus. In conjunction, these studies revealed that the behavioral changes of infected rodents were due to a specific olfactory mechanism and not due to general malaise. Furthermore, this response is not binary – it is moderated by the amount of “cat” in the environment. This supports the notion that Toxoplasma optimizes the costs and benefits of behavior manipulation by balancing the induced response.
While the literature suggests a seemingly elegant solution to the mystery of modified behavior in the rodent-Toxoplasma gondii host-parasite system, the vagaries of human infection are more complex and difficult to explain. Berdoy et al. suggest that the biochemical mechanisms in the rat brain are primitively analogous to the human brain, citing both species’ omnivorous nature as underlying the innate fear responses of the amygdala. This, and other hypotheses of human behavioral modification, will form the remainder of my discussion.
“Is insanity due to a microbe?” T. gondii in H. sapiens
This 1896 title of a Scientific American article sparked a century long search for the link between parasites and schizophrenia. Many erratic behaviors have been observed in humans with toxoplasmosis. These include increased jealousy, introspection, boredom, suspicion, emotional instability and decreased psychomotor activity, reaction times, self esteem, and regard for social rules in men; whereas women tend to show increased self-esteem, intelligence, awareness, amiability, attention to others, loyalty, respect for social rules, and cordiality (Flegr et al. 2007).
Perhaps the most interesting behavioral observation of T. gondii in humans is the link between toxoplasmosis and schizophrenia. According to Henriquez et al., the prevalence of T. gondii antibodies in schizophrenic patients is more significant than any other environmental or genetic factor previously mentioned. This relationship is not well understood; after all, correlation does not imply causation. There is no agreement whether this increased incidence is due to the behavior of schizophrenic patients with respect to their domestic feline house pets, or whether a symptom of congenital toxoplasmosis is the eventual development of schizophrenia (Torrey and Yolken, 2003). Even so, a number of interesting results have arisen upon discovery of this relationship. First is the discovery that anti-psychotic drugs commonly used for treatment of schizophrenia, such as haloperidol and valproic acid, can be used to block the loss of fear in infected rats (Webster et al. 2006). Furthermore, these drugs can be used to successfully treat toxoplasmosis (Torrey and Yolken 2003). Finally, knowledge of the host and vector behavior of T. gondii can be used to effectively prevent transmission of the parasite between humans and their cats, especially in pregnant women and immunocompromised individuals.
While parallels can be drawn between behavior modification in rats and humans due to infection with Toxoplasma gondii, I argue that the behavioral modification theory of parasitism cannot be applied to humans in the same way that it has been proven in rats. For one, relocation into a human host occurs at a significant loss to the parasite. Furthermore, T. gondii do not alter human behavior in a way that appreciably increases the likelihood of predation and thus completion of sexual reproduction in Felidae. Even so, the neuropsychiatric affects of Toxoplasma in humans remains a rich and interesting area for further research. Given the high prevalence and incidence of Toxoplasma worldwide, results from these studies may have significant and far-reaching clinical and public health implications.
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