Evidence for finely-regulated asynchronous growth of Toxoplasma gondii cysts based on data-driven model selection.

Toxoplasma gondii establishes a chronic infection by forming cysts preferentially in the brain. This chronic infection is one of the most common parasitic infections in humans and can be reactivated to develop life-threatening toxoplasmic encephalitis in immunocompromised patients. Host-pathogen interactions during the chronic infection include growth of the cysts and their removal by both natural rupture and elimination by the immune system. Analyzing these interactions is important for understanding the pathogenesis of this common infection. We developed a differential equation framework of cyst growth and employed Akaike Information Criteria (AIC) to determine the growth and removal functions that best describe the distribution of cyst sizes measured from the brains of chronically infected mice. The AIC strongly support models in which T. gondii cysts grow at a constant rate such that the per capita growth rate of the parasite is inversely proportional to the number of parasites within a cyst, suggesting finely-regulated asynchronous replication of the parasites. Our analyses were also able to reject the models where cyst removal rate increases linearly or quadratically in association with increase in cyst size. The modeling and analysis framework may provide a useful tool for understanding the pathogenesis of infections with other cyst producing parasites.

An agent-based model for the transmission dynamics of Toxoplasma gondii.

Toxoplasma gondii (T. gondii) is a unicellular protozoan that infects up to one-third of the world's human population. Numerous studies revealed that a latent infection of T. gondii can cause life-threatening encephalitis in immunocompromised people and also has significant effects on the behavior of healthy people and animals. However, the overall transmission of T. gondii has not been well understood although many factors affecting this process have been found out by different biologists separately. Here we synthesize what is currently known about the natural history of T. gondii by developing a prototype agent-based model to mimic the transmission process of T. gondii in a farm system. The present model takes into account the complete life cycle of T. gondii, which includes the transitions of the parasite from cats to environment through feces, from contaminated environment to mice through oocysts, from mice to cats through tissue cysts, from environment to cats through oocysts as well as the vertical transmission among mice. Although the current model does not explicitly include humans and other end-receivers, the effect of the transition to end-receivers is estimated by a developed infection risk index. The current model can also be extended to include human activities and thus be used to investigate the influences of human management on disease control. Simulation results reveal that most cats are infected through preying on infected mice while mice are infected through vertical transmission more often than through infection with oocysts, which clearly suggests the important role of mice during the transmission of T. gondii. Furthermore, our simulation results show that decreasing the number of mice on a farm can lead to the eradication of the disease and thus can lower the infection risk of other intermediate hosts on the farm. In addition, with the assumption that the relation between virulence and transmission satisfies a normal function, we show that intermediate virulent lineages (type II) can sustain the disease most efficiently, which can qualitatively agree with the fact that the evolution of the parasite favors intermediate virulence. The effects of other related factors on transmission, including the latent period and imprudent behavior of mice, and prevention strategies are also studied based on the present model.