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Viruses 2018, 10(5), 243; https://doi.org/10.3390/v10050243

Characterization of an N-Terminal Non-Core Domain of RAG1 Gene Disrupted Syrian Hamster Model Generated by CRISPR Cas9

1
Department of Pathology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
2
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322, USA
3
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
4
Department of Animal Science, Division of Applied Life Science (BK21Plus), Graduate School of Gyeongsang National University, Jinju 52828, Korea
5
Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea
6
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
7
Auratus Bio, LLC., Canton, SD 57104, USA
*
Authors to whom correspondence should be addressed.
Received: 20 March 2018 / Revised: 25 April 2018 / Accepted: 3 May 2018 / Published: 6 May 2018
(This article belongs to the Special Issue Applications of CRISPR Technology in Virology 2018)
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Abstract

The accumulating evidence demonstrates that Syrian hamsters have advantages as models for various diseases. To develop a Syrian hamster (Mesocricetus auratus) model of human immunodeficiency caused by RAG1 gene mutations, we employed the CRISPR/Cas9 system and introduced an 86-nucleotide frameshift deletion in the hamster RAG1 gene encoding part of the N-terminal non-core domain of RAG1. Histological and immunohistochemical analyses demonstrated that these hamsters (referred herein as RAG1-86nt hamsters) had atrophic spleen and thymus, and developed significantly less white pulp and were almost completely devoid of splenic lymphoid follicles. The RAG1-nt86 hamsters had barely detectable CD3+ and CD4+ T cells. The expression of B and T lymphocyte-specific genes (CD3γ and CD4 for T cell-specific) and (CD22 and FCMR for B cell-specific) was dramatically reduced, whereas the expression of macrophage-specific (CD68) and natural killer (NK) cell-specific (CD94 and KLRG1) marker genes was increased in the spleen of RAG1-nt86 hamsters compared to wildtype hamsters. Interestingly, despite the impaired development of B and T lymphocytes, the RAG1-86nt hamsters still developed neutralizing antibodies against human adenovirus type C6 (HAdV-C6) upon intranasal infection and were capable of clearing the infectious viruses, albeit with slower kinetics. Therefore, the RAG1-86nt hamster reported herein (similar to the hypomorphic RAG1 mutations in humans that cause Omenn syndrome), may provide a useful model for studying the pathogenesis of the specific RAG1-mutation-induced human immunodeficiency, the host immune response to adenovirus infection and other pathogens as well as for evaluation of cell and gene therapies for treatment of this subset of RAG1 mutation patients. View Full-Text
Keywords: Syrian hamster; RAG1; SCID; CRISPR/Cas9; animal model; adenovirus infection Syrian hamster; RAG1; SCID; CRISPR/Cas9; animal model; adenovirus infection
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Miao, J.; Ying, B.; Li, R.; Tollefson, A.E.; Spencer, J.F.; Wold, W.S.M.; Song, S.-H.; Kong, I.-K.; Toth, K.; Wang, Y.; Wang, Z. Characterization of an N-Terminal Non-Core Domain of RAG1 Gene Disrupted Syrian Hamster Model Generated by CRISPR Cas9. Viruses 2018, 10, 243.

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