The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis
The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis
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DOI：
10.1128/iai.00348-16
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发表时间：
2016-10-01
影响因子：
3.1
通讯作者：
Singer, Steven M.
中科院分区：
文献类型：
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作者：
Keselman, Aleksander;Li, Erqiu;Singer, Steven M.
十二指肠贾第鞭毛虫是一种非侵入性肠道病原体，部分通过降低肠道双糖酶活性来损害宿主的消化功能。这种酶缺乏症在小鼠中被证明需要CD8(+) T细胞。我们最近发现宿主免疫反应和寄生虫菌株都影响鼠贾第虫病期间的双糖酶水平。然而，在该研究中，高剂量抗生素被用于促进感染，因此我们决定系统地检查抗生素使用对贾第虫病小鼠模型的发病机制和免疫反应的影响。我们发现抗生素治疗没有明显增加寄生虫负担，但显著限制了感染小鼠观察到的双糖酶缺乏症。此外，虽然感染小鼠在小肠固有层中有更多活化的CD8(+) α β T细胞，但在抗生素治疗的小鼠中没有这种增加。感染还导致固有层中CD4(+) α - β T细胞数量增加和表达γ δ的T细胞受体上皮内淋巴细胞（IEL）的激活，但这些变化不受抗生素的影响。最后，我们发现活化的CD8(+) T细胞表达γ干扰素（ifn - γ）和颗粒酶，但颗粒酶不是蔗糖酶缺乏所必需的。我们得出结论，CD8(+) T细胞在贾第虫病中通过抗生素敏感过程被激活，并有助于降低蔗糖酶活性。这是第一个直接证明CD8(+) T细胞和γ δ T细胞在贾第鞭毛虫感染期间活化的数据。这些数据还表明，抗生素治疗对肠道微生物群的破坏可阻止贾第虫病的病理性CD8(+) T细胞活化。
Giardia duodenalis is a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8(+) T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8(+) alpha beta T cells in the small intestinal lamina propria, this increase was absent in antibiotic-treated mice. Infection also led to increased numbers of CD4(+) alpha beta T cells in the lamina propria and activation of T cell receptor gamma delta-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8(+) T cells express gamma interferon (IFN-gamma) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8(+) T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8(+) T cells and gamma delta T cells during Giardia infections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8(+) T cell activation in giardiasis.