Development and characterization of type I interferon receptor knockout sheep: A model for viral immunology and reproductive signaling

被引:6
|
作者
Davies, Christopher J. [1 ,2 ]
Fan, Zhiqiang [1 ]
Morgado, Kira P. [1 ,2 ]
Liu, Ying [1 ]
Regouski, Misha [1 ]
Meng, Qinggang [1 ]
Thomas, Aaron J. [1 ,2 ]
Yun, Sang-Im [1 ]
Song, Byung-Hak [1 ]
Frank, Jordan C. [1 ]
Perisse, Iuri V. [1 ]
Van Wettere, Arnaud [1 ]
Lee, Young-Min [1 ]
Polejaeva, Irina A. [1 ]
机构
[1] Utah State Univ, Dept Anim Dairy & Vet Sci, Coll Agr & Appl Sci, Logan, UT 84322 USA
[2] Utah State Univ, Ctr Integrated Biosyst, Coll Agr & Appl Sci, Logan, UT 84322 USA
基金
美国食品与农业研究所;
关键词
animal models; interferon receptor knockout; type I interferons; innate immunity; Zika virus; recognition of pregnancy; sheep; CRISPR/Cas9; CONCEPTUS SECRETORY PROTEINS; ZIKA VIRUS; GENE-EXPRESSION; OVINE; OXYTOCIN; TAU; PROGESTERONE; PREGNANCY; CLONING; ALPHA;
D O I
10.3389/fgene.2022.986316
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Type I interferons (IFNs) initiate immune responses to viral infections. Their effects are mediated by the type I IFN receptor, IFNAR, comprised of two subunits: IFNAR1 and IFNAR2. One or both chains of the sheep IFNAR were disrupted in fetal fibroblast lines using CRISPR/Cas9 and 12 lambs were produced by somatic cell nuclear transfer (SCNT). Quantitative reverse transcription-polymerase chain reaction for IFN-stimulated gene expression showed that IFNAR deficient sheep fail to respond to IFN-alpha. Furthermore, fibroblast cells from an IFNAR2 ( -/- ) fetus supported significantly higher levels of Zika virus (ZIKV) replication than wild-type fetal fibroblast cells. Although many lambs have died from SCNT related problems or infections, one fertile IFNAR2 ( -/- ) ram lived to over 4 years of age, remained healthy, and produced more than 80 offspring. Interestingly, ZIKV infection studies failed to demonstrate a high level of susceptibility. Presumably, these sheep compensated for a lack of type I IFN signaling using the type II, IFN-gamma and type III, IFN-lambda pathways. These sheep constitute a unique model for studying the pathogenesis of viral infection. Historical data supports the concept that ruminants utilize a novel type I IFN, IFN-tau, for pregnancy recognition. Consequently, IFNAR deficient ewes are likely to be infertile, making IFNAR knockout sheep a valuable model for studying pregnancy recognition. A breeding herd of 32 IFNAR2 ( +/- ) ewes, which are fertile, has been developed for production of IFNAR2 ( -/- ) sheep for both infection and reproduction studies.
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页数:16
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