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.

生活在恰加斯病（Chagas disease）活跃虫媒传播区域的人群，与其病原体克氏锥虫（Trypanosoma cruzi）存在多次接触机会。克氏锥虫的重复感染至少在动物模型中已被证实可导致寄生虫血症水平降低，甚至几乎无法检测。在人类群体中，尽管普遍认为重复感染会通过增加该病慢性表现的风险而对公共卫生产生重大影响，但目前关于其发生频率以及疾病进程中寄生虫再次接种的时间节点，相关定量认知仍十分匮乏。本研究构建了基于随机智能体的模型（stochastic agent-based models），旨在达成两个目标：其一，估算人类群体中寄生虫再次接种的速率；其二，依据原发感染后适应性免疫应答的不同假说，评估疾病急性与慢性阶段的重复感染发生频率。研究采用混合遗传算法（hybrid genetic algorithm），将模型拟合至阿根廷乡村的流行病学数据——该地区人群感染不同基因型克氏锥虫的混合感染率高达56%。为解释这一感染比例，最优模型预测：每名个体每年的重复感染率为0.032（95%置信区间：0.008–0.042），其中98.4%的重复感染发生于慢性阶段。此外，至少20%的再次接种事件中，寄生虫可逃逸原发感染后激活的适应性免疫应答。基于此类较低的年感染率，在通常漫长的慢性疾病进程中，个体5年和30年后的重复感染风险分别约为14%（4%–18%）与60%（21%–70%），多数个体总体仅会被重复感染1–3次。相较于高效的适应性免疫应答，这种较低的感染率更可通过粪传途径（stercorarian mode of transmission）的低效性得到解释。上述估算结果对于疫苗研发，以及我们理解流行区域感染者罹患慢性疾病表现的更高风险，均具有重要参考价值。