Trypanosoma cruzi Infection through the Oral Route Promotes a Severe Infection in Mice: New Disease Form from an Old Infection?
Trypanosoma cruzi Infection through the Oral Route Promotes a Severe Infection in Mice: New Disease Form from an Old Infection?
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DOI：
10.1371/journal.pntd.0003849
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发表时间：
2015-06-01
影响因子：
3.8
通讯作者：
de Meis, Juliana
中科院分区：
文献类型：
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作者：
Barreto-de-Albuquerque, Juliana;Silva-dos-Santos, Danielle;de Meis, Juliana
拉丁美洲国家已有恰加斯病经口传播的记录。然而，对这种形式感染的病理生理学的重要研究却很缺乏。少数调查口腔途径感染的研究忽视了口腔接种（口腔感染，OI）或灌胃接种（胃肠感染，GI）代表不同的感染途径，但两者都在急性感染期间显示出明显的寄生虫血症和心脏寄生。在此，使用 5x10(4) 培养物衍生的克氏锥虫锥鞭毛体对 BALB/c 小鼠进行急性 OI 或 GI 感染。 OI 小鼠比胃肠道小鼠表现出更高的寄生虫血症和死亡率。心脏组织病理学显示，胃肠道小鼠有较大面积的浸润，而成骨不全动物的肝脏病变更严重，血清丙氨酸转氨酶和天冬氨酸转氨酶含量较高。还观察到了不同的细胞因子模式，因为 OI 小鼠比胃肠道动物表现出更高的促炎细胞因子（IFN-γ、TNF）血清水平。实时 PCR 证实，与 GI 组相比，OI 组心脏组织中 TNF、IFN-γ 以及 IL-10 的表达更高。相反，胃肠道动物的 TGF-β 和 IL-17 血清水平较高。免疫标记显示巨噬细胞是感染小鼠中 TNF 的主要组织来源。在 OI 小鼠中观察到的高死亡率与 TNF 血清升高平行，抗 TNF 治疗可抑制 TNF 血清升高。此外，GI 小鼠与 OI 小鼠之间的易感性差异与宿主反应的相关性比胃 pH 对寄生虫的影响更明显，因为氢氧化镁处理的小鼠的感染显示出相似的结果。总体而言，本研究提供了确凿的证据，表明寄生虫进入的初始部位严重影响宿主免疫反应和疾病结果。鉴于口腔恰加斯病暴发的发生，我们的研究结果对当前对自然病程和宿主与寄生虫关系的看法提出了重要的启示。
Oral transmission of Chagas disease has been documented in Latin American countries. Nevertheless, significant studies on the pathophysiology of this form of infection are largely lacking. The few studies investigating oral route infection disregard that inoculation in the oral cavity (Oral infection, OI) or by gavage (Gastrointestinal infection, GI) represent different infection routes, yet both show clear-cut parasitemia and heart parasitism during the acute infection. Herein, BALB/c mice were subjected to acute OI or GI infection using 5x10(4) culture-derived Trypanosoma cruzi trypomastigotes. OI mice displayed higher parasitemia and mortality rates than their GI counterparts. Heart histopathology showed larger areas of infiltration in the GI mice, whereas liver lesions were more severe in the OI animals, accompanied by higher Alanine Transaminase and Aspartate Transaminase serum contents. A differential cytokine pattern was also observed because OI mice presented higher pro-inflammatory cytokine (IFN-gamma, TNF) serum levels than GI animals. Real-time PCR confirmed a higher TNF, IFN-gamma, as well as IL-10 expression in the cardiac tissue from the OI group compared with GI. Conversely, TGF-beta and IL-17 serum levels were greater in the GI animals. Immunolabeling revealed macrophages as the main tissue source of TNF in infected mice. The high mortality rate observed in the OI mice paralleled the TNF serum rise, with its inhibition by an anti-TNF treatment. Moreover, differences in susceptibility between GI versus OI mice were more clearly related to the host response than to the effect of gastric pH on parasites, since infection in magnesium hydroxide-treated mice showed similar results. Overall, the present study provides conclusive evidence that the initial site of parasite entrance critically affects host immune response and disease outcome. In light of the occurrence of oral Chagas disease outbreaks, our results raise important implications in terms of the current view of the natural disease course and host-parasite relationship.