A behavioral model for Toxoplasmosis gondii infection
Bing Mei Wang
05424674
D. Scott Smith, MD
Human Biology 153
26 February 2010
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Introduction
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
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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.
Background
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.
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Figure 1. Life Cycle of Toxoplasma gondii (Tenter et al. 2000)
Figure 2: Modes of Transmission (Tenter et al. 2000)
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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.
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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, Hrdà 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
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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
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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 costbeneficial. 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.
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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.
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“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
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the parasite between humans and their cats, especially in pregnant women and
immunocompromised individuals.
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Conclusion
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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