Toxoplasma gondii infection triggers chronic cachexia and sustained commensal dysbiosis in mice
Toxoplasma gondii infection triggers chronic cachexia and sustained commensal dysbiosis in mice
复制标题
DOI：
10.1371/journal.pone.0204895
复制
发表时间：
2018-10-31
期刊：
影响因子：
3.7
通讯作者：
Ewald, Sarah E.
中科院分区：
文献类型：
--
作者：
Hatter, Jessica A.;Kouche, Yue Moi;Ewald, Sarah E.
刚地弓形虫是一种原生动物寄生虫，在啮齿动物和猫科动物之间具有捕食介导的传播周期。中间宿主通过食用寄生虫囊肿获得弓形虫，弓形虫侵入小肠，全身传播，最终在宿主脑和肌肉中建立终身慢性感染。在这里，我们表明弓形虫感染可以引发一种严重形式的持续恶病质：一种进行性瘦体重减轻的疾病，是癌症、慢性病和许多感染死亡的因果预测因子。弓形虫恶病质的特征是急性厌食症、全身炎症和体重减少20%。尽管小鼠从高峰病的症状中恢复过来，但它们无法恢复肌肉质量或内脏脂肪储备。我们想知道在急性时间点观察到的肠道微环境损伤是否在慢性感染中持续存在，从而可能在维持恶病质中发挥作用。我们发现，在急性感染期间，寄生虫在空肠远端/回肠近端同一区域复制，诱导继发性淋巴样结构的发展和严重的局部炎症。感染后5周小肠病理消失。然而，在慢性感染中，共生种群的变化，特别是梭状芽孢杆菌的生长，是持续的。重要的是，与感染小鼠同住的未感染动物在共生菌群中表现出类似的变化，但从未表现出恶病质的症状，这表明改变的共生菌群不足以单独解释恶病质表型。这些研究表明，弓形虫感染是研究慢性恶病质发展、病理和潜在逆转的免疫-代谢相互作用的一个新的和强大的模型。
Toxoplasma gondii is a protozoan parasite with a predation-mediated transmission cycle between rodents and felines. Intermediate hosts acquire Toxoplasma by eating parasite cysts which invade the small intestine, disseminate systemically and finally establish host life-long chronic infection in brain and muscles. Here we show that Toxoplasma infection can trigger a severe form of sustained cachexia: a disease of progressive lean weight loss that is a causal predictor of mortality in cancer, chronic disease and many infections. Toxoplasma cachexia is characterized by acute anorexia, systemic inflammation and loss of 20% body mass. Although mice recover from symptoms of peak sickness, they fail to regain muscle mass or visceral adipose depots. We asked whether the damage to the intestinal microenvironment observed at acute time points was sustained in chronic infection and could thereby play a role in sustaining cachexia. We found that parasites replicate in the same region of the distal jejunum/proximal ileum throughout acute infection, inducing the development of secondary lymphoid structures and severe, regional inflammation. Small intestine pathology was resolved by 5 weeks post-infection. However, changes in the commensal populations, notably an outgrowth of Clostridia spp., were sustained in chronic infection. Importantly, uninfected animals co-housed with infected mice display similar changes in commensal microflora but never display symptoms of cachexia, indicating that altered commensals are not sufficient to explain the cachexia phenotype alone. These studies indicate that Toxoplasma infection is a novel and robust model to study the immune-metabolic interactions that contribute to chronic cachexia development, pathology and potential reversal.