Parasite dissemination and the pathogenesis of toxoplasmosis

Many pathogens are restricted to the site of colonization or have a distribution restricted to specific tissues. For others, the ability to disseminate from the initial point of infection and invade different niches is an integral part of their biology. For example, various protozoan and helminth parasites need to migrate through distinct host tissues to complete their life cycles. Thus, the success of Plasmodium is dependent on the ability of different developmental stages to migrate from the skin to the liver, and finally to the blood for transmission. Similarly, Schistosoma mansoni undergoes a protracted migration that starts in the skin and proceeds through multiple tissues, including the lungs, before adults pair in the mesenteric venules, allowing eggs to exit through the intestine. For these parasites, the clinical features and tissues affected are a consequence of the natural progression of the infection. For other parasites, inappropriate migration or dissemination forms the basis for disease and this is illustrated by the ability of Entamoeba histolytica to cross from the intestine and cause the development of liver abscesses. Similarly, there are several helminthes and nematodes that, when in inappropriate hosts, fail to develop fully and continuously migrate through tissues such as the brain where they can cause extensive tissue damage. For all of these cases, the ability of the parasites to cross biological barriers at either the point of entry or subsequently within the host is key to reproductive success or to the pathology that can accompany these diseases. Similar principles apply to Toxoplasma gondii, a major pathogen of public health importance that causes a chronic infection in approximately one third of the world population [1, 2]. The ability of T. gondii to invade many tissues is an important element that contributes to the spectrum of diseases that can be associated with this organism. Thus, following the ingestion of oocysts or tissue cysts of T. gondii, this organism infects its host in the small intestine and converts to the tachyzoite form, which then disseminates rapidly to almost all tissues, including muscle, brain, eyes, liver, placenta and lungs. Typically, this infection leads to a robust innate and adaptive response that is characterized by the production of IFN-γ by NK and T cells, which leads to the control of the acute phase (for review see [3]). These events are associated with immune pressure that drives the parasite to develop into a chronic, usually asymptomatic stage, where this organism persists as bradyzoites in cyst form within multiple tissues, most notably the brain, eye and muscle. Associated with this process of dissemination are a wide variety of clinical manifestations. The first recognized example involved the identification of T. gondii in a human fetus [4]. Subsequently, it was recognized that, in the case of primary T. gondii infection during pregnancy, the invasion of the placenta allows the parasites to infect the fetus and can lead to abortion, malformation of the fetus and congenital toxoplasmosis. Despite the fact that Toxoplasma affects multiple tissues, the most common clinical manifestations of toxoplasmosis involve the brain and eye. Thus, even in adults, primary infection can present as chorioretinitis and, in chronically infected individuals who develop defects in T cell function, such as during HIV infection or following chemotherapy, the reactivation of cysts in the brain can lead to Toxoplasmic encephalitis (TE). The basis for this tropism is uncertain – but could be a consequence of the immune privileged nature of these sites. Alternatively, there are multiple instances of parasites that affect the nervous system of their hosts to alter behaviour and promote predation of intermediate hosts [5–7]. For example, Dicrocoelium dendriticum, a flatworm, alters the behaviour of its intermediate host, the ant, to improve the chances of parasite transmission to herbivores (for an entertaining review on parasites and behaviour see [8]). Indeed, behavioural studies using mice and rats indicated that chronic T. gondii infection results in a specific switch from an aversion to cat urine to an attraction, presumably a change in behaviour that would lead to increased predation of infected rodents by cats, the definitive host, allowing sexual reproduction in the cat intestine [9]. Regardless of the biological consequences of the dissemination of T. gondii, many questions remain about the cellular basis for these events. For many pathogens, it is clear that an effective localized immune response can limit replication and the ability of a micro-organism to disseminate out of these focal areas would decrease the likelihood of the infection being completely eliminated. While the motility of some extracellular pathogens may allow these organisms to avoid the cellular components of the immune system, there are also examples where immune populations are hijacked for the success of the pathogen. Unlike other organ systems, the immune system is largely motile: cells detect foreign agents and travel to lymphoid organs for the activation and generation of cell-mediated and humoral responses, primed effector cells can traffic into and out of sites of inflammation. The aim of this review is provide an overview of our current understanding the role of the immune system in these events that lead to the dissemination of T. gondii and how this impacts the pathogenesis of this infection.