Bacterial and Pneumocystis Infections in the Lungs of Gene-Knockout Rabbits with Severe Combined Immunodeficiency.
Bacterial and Pneumocystis Infections in the Lungs of Gene-Knockout Rabbits with Severe Combined Immunodeficiency.
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DOI：
10.3389/fimmu.2018.00429
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发表时间：
2018
影响因子：
7.3
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Song J;Wang G;Hoenerhoff MJ;Ruan J;Yang D;Zhang J;Yang J;Lester PA;Sigler R;Bradley M;Eckley S;Cornelius K;Chen K;Kolls JK;Peng L;Ma L;Chen YE;Sun F;Xu J
利用CRISPR/Cas9基因编辑技术，我们最近培育出了一批免疫功能基因突变的兔，包括FOXN1、PRKDC、RAG1、RAG2和IL2RG。7只方正基因敲除兔(F0)和3只雄性IL2RG缺失(−/y)F1动物表现出严重的联合免疫缺陷，表现为胸腺和脾白髓缺乏或明显发育不良，外周血中缺乏未成熟和成熟的T、B淋巴细胞。全血细胞分析显示严重的白细胞减少和淋巴细胞减少伴随严重的中性粒细胞减少。在没有预防性抗生素的情况下，SCID兔在断奶后普遍死于肺部感染。病理检查发现几只动物有严重的嗜异嗜性支气管炎，但经组织学检查和肺孢子虫基因的聚合酶链式反应分析证实，所有动物的肺部病变都有一个一致的特征，即由米氏肺孢子虫引起的严重间质性肺炎。本研究结果提示，这些SCID兔可作为人类SCID的模型，用于研究SCID的发病机制及基因和药物治疗的发展。
Using the CRISPR/Cas9 gene-editing technology, we recently produced a number of rabbits with mutations in immune function genes, including FOXN1, PRKDC, RAG1, RAG2, and IL2RG. Seven founder knockout rabbits (F0) and three male IL2RG null (−/y) F1 animals demonstrated severe combined immunodeficiency (SCID), characterized by absence or pronounced hypoplasia of the thymus and splenic white pulp, and absence of immature and mature T and B-lymphocytes in peripheral blood. Complete blood count analysis showed severe leukopenia and lymphocytopenia accompanied by severe neutrophilia. Without prophylactic antibiotics, the SCID rabbits universally succumbed to lung infections following weaning. Pathology examination revealed severe heterophilic bronchopneumonia caused by Bordetella bronchiseptica in several animals, but a consistent feature of lung lesions in all animals was a severe interstitial pneumonia caused by Pneumocystis oryctolagi, as confirmed by histological examination and PCR analysis of Pneumocystis genes. The results of this study suggest that these SCID rabbits could serve as a useful model for human SCID to investigate the disease pathogenesis and the development of gene and drug therapies.