Autophagy plays a protective role against Trypanosoma cruzi infection in mice

Autophagy is a catabolic pathway required for cellular and organism homeostasis. Autophagy participates in the innate and adaptive immune responses at different levels. Xenophagy is a class of selective autophagy that involves the elimination of intracellular pathogens. Trypanosoma cruzi is the causative agent of Chagas, a disease that affects 8 million individuals worldwide. Previously, our group has demonstrated that autophagy participates in the invasion of T. cruzi in non-phagocytic cells. In this work we have studied the involvement of autophagy in the development of T. cruzi infection in mice. Beclin-1 is a protein essential for autophagy, required for autophagosome biogenesis and maturation. We have performed an acute model of infection on the autophagic deficient Beclin-1 heterozygous knock-out mice (Bcln±) and compared to control Bcln+/+ animals. In addition, we have analyzed the infection process in both peritoneal cells and RAW macrophages. Our results have shown that the infection was more aggressive in the autophagy-deficient mice, which displayed higher numbers of parasitemia, heart´s parasitic nests and mortality rates. We have also found that peritoneal cells derived from Bcln± animals and RAW macrophages treated with autophagy inhibitors displayed higher levels of infection compared to controls. Interestingly, free cytosolic parasites recruited LC3 protein and other markers of xenophagy in control compared to autophagy-deficient cells. Taken together, these data suggest that autophagy plays a protective role against T. cruzi infection in mice, xenophagy being one of the processes activated as part of the repertoire of immune responses generated by the host.

自噬（autophagy）是维持细胞与机体稳态所必需的分解代谢途径。自噬在不同层面参与固有免疫与适应性免疫应答。异型自噬（xenophagy）是一类选择性自噬，其功能为清除胞内病原体。克氏锥虫（Trypanosoma cruzi）是恰加斯病的致病原，该疾病在全球范围内影响约800万人群。此前本团队已证实，自噬参与克氏锥虫对非吞噬细胞的侵袭过程。本研究探讨了自噬在小鼠克氏锥虫感染进程中的作用。Beclin-1是一种对自噬至关重要的蛋白质，参与自噬体的生物发生与成熟过程。我们构建了自噬缺陷型Beclin-1杂合敲除小鼠（Bcln±）的急性感染模型，并与野生型对照小鼠（Bcln+/+）进行对比。此外，我们分析了腹腔细胞与RAW巨噬细胞的感染过程。实验结果显示，自噬缺陷小鼠的感染进程更为凶险，其虫血症水平、心脏寄生灶数量及死亡率均显著升高。我们还发现，相较于对照组，源自Bcln±小鼠的腹腔细胞以及经自噬抑制剂处理的RAW巨噬细胞，其感染程度更高。值得注意的是，相较于自噬缺陷细胞，对照组中的游离胞质寄生虫会招募LC3蛋白及其他异型自噬标志物。综上，本研究数据表明，自噬对小鼠克氏锥虫感染具有保护作用，而异型自噬作为宿主免疫应答反应组分之一，是其中发挥功能的关键过程。