Epidemiological modeling of Trypanosoma cruzi: Low stercorarian transmission and failure of host adaptive immunity explain the frequency of mixed infections in humans

People living in areas with active vector-borne transmission of Chagas disease have multiple contacts with its causative agent, Trypanosoma cruzi. Reinfections by T. cruzi are possible at least in animal models leading to lower or even hardly detectable parasitaemia. In humans, although reinfections are thought to have major public health implications by increasing the risk of chronic manifestations of the disease, there is little quantitative knowledge about their frequency and the timing of parasite re-inoculation in the course of the disease. Here, we implemented stochastic agent-based models i) to estimate the rate of re-inoculation in humans and ii) to assess how frequent are reinfections during the acute and chronic stages of the disease according to alternative hypotheses on the adaptive immune response following a primary infection. By using a hybrid genetic algorithm, the models were fitted to epidemiological data of Argentinean rural villages where mixed infections by different genotypes of T. cruzi reach 56% in humans. To explain this percentage, the best model predicted 0.032 (0.008–0.042) annual reinfections per individual with 98.4% of them occurring in the chronic phase. In addition, the parasite escapes to the adaptive immune response mounted after the primary infection in at least 20% of the events of re-inoculation. With these low annual rates, the risks of reinfection during the typically long chronic stage of the disease stand around 14% (4%-18%) and 60% (21%-70%) after 5 and 30 years, with most individuals being re-infected 1–3 times overall. These low rates are better explained by the weak efficiency of the stercorarian mode of transmission than a highly efficient adaptive immune response. Those estimates are of particular interest for vaccine development and for our understanding of the higher risk of chronic disease manifestations suffered by infected people living in endemic areas.Author summary: Chagas disease is caused by a unicellular parasite mainly transmitted by blood-feeding bugs. The disease starts with an acute phase when the parasite multiplies in tissues. The immune system is then activated and almost clears the parasites before the host enters the chronic phase of the disease. As hosts remain exposed to the vectors, secondary contacts may result in re-inoculation with the parasite. The re-inoculated parasites then have to face an adaptive immune response that may prevent reinfection. There is little quantitative knowledge about the frequency of such re-inoculation and the efficiency of the immune system to prevent them. Since reinfections can lead to people carrying two or more strains of the parasite, we can potentially infer on the frequency of reinfection from the detection of such mixed infections. We fitted agent-based models to field data to estimate the frequency of reinfection in humans and its timing after primary infection. Our models predicted that most reinfections occur during the chronic phase as the adaptive immune response fails to prevent them in 20% of re-inoculations. Such a rate of failure is particularly important as reinfections are thought to increase the risk of heart damage in the chronic phase of the disease.