Autophagy plays a protective role against <i>Trypanosoma cruzi</i> 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. <i>Trypanosoma cruzi</i> 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 <i>T. cruzi</i> in non-phagocytic cells. In this work we have studied the involvement of autophagy in the development of <i>T. cruzi</i> 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 <i>Beclin-1</i> 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 <i>T. cruzi</i> infection in mice, xenophagy being one of the processes activated as part of the repertoire of immune responses generated by the host.细胞自噬（autophagy）是维持细胞与机体稳态所必需的分解代谢途径，其在多个层面参与固有免疫与适应性免疫应答。异体吞噬（xenophagy）属于一类选择性自噬，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，细胞自噬参与克氏锥虫对非吞噬细胞的入侵过程。本研究探究了自噬在小鼠克氏锥虫感染进程中的作用。Beclin-1是自噬的必需蛋白，对自噬体的生物发生与成熟至关重要。我们构建了自噬缺陷的Beclin-1杂合敲除小鼠（Bcln±）急性感染模型，并以野生型Bcln+/+动物作为对照。此外，我们分别分析了腹膜细胞与RAW巨噬细胞中的感染过程。研究结果显示，自噬缺陷小鼠的感染进程更为凶险，表现为更高的寄生虫血症水平、心脏寄生虫病灶数量以及更高的死亡率。我们还发现，源自Bcln±小鼠的腹膜细胞，以及经自噬抑制剂处理的RAW巨噬细胞，其感染水平均高于对照组。值得注意的是，与自噬缺陷细胞相比，对照组中的游离胞浆寄生虫会募集LC3蛋白及其他异体吞噬相关标志物。综上，上述数据表明细胞自噬对小鼠克氏锥虫感染具有保护作用，而异体吞噬是宿主激活的免疫反应谱中的关键过程之一。