Generation and characterization of an Il2rg knockout Syrian hamster model for XSCID and HAdV-C6 infection in immunocompromised patients.

Rong Li,Jinxin Miao,Baoling Ying,Yanan Liu,James D Brien,William S M Wold,Jacqueline F Spencer,Karoly Toth,Yaohe Wang,Zhongde Wang,Ann E Tollefson

doi:10.1242/dmm.044602

Abstract

ABSTRACTModel animals are indispensable for the study of human diseases, and in general, of complex biological processes. The Syrian hamster is an important model animal for infectious diseases, behavioral science and metabolic science, for which more experimental tools are becoming available. Here, we describe the generation and characterization of an interleukin-2 receptor subunit gamma (Il2rg) knockout (KO) Syrian hamster strain. In humans, mutations in IL2RG can result in a total failure of T and natural killer (NK) lymphocyte development and nonfunctional B lymphocytes (X-linked severe combined immunodeficiency; XSCID). Therefore, we sought to develop a non-murine model to study XSCID and the infectious diseases associated with IL2RG deficiency. We demonstrated that the Il2rg KO hamsters have a lymphoid compartment that is greatly reduced in size and diversity, and is impaired in function. As a result of the defective adaptive immune response, Il2rg KO hamsters developed a more severe human adenovirus infection and cleared virus less efficiently than immune competent wild-type hamsters. Because of this enhanced virus replication, Il2rg KO hamsters developed more severe adenovirus-induced liver pathology than wild-type hamsters. This novel hamster strain will provide researchers with a new tool to investigate human XSCID and its related infections.

Highlights

Advancements have been made in the application of in vitro and in silico systems, the complexity of most diseases can be captured only in animal models
We found a significant increase of a macrophage- and dendritic cell (DC)-specific mRNA (Cd68) in the livers of HAdV-C6-infected interleukin-2 receptor subunit gamma (Il2rg) KO hamsters compared to wild-type animals (Fig. 6A), and, as expected, significantly lower expression of T lymphocyte- (Fig. 6C,D) and natural killer (NK) cell-specific (Fig. 6B) transcripts
The Syrian hamster is an extremely important animal model for several human infectious diseases either because a pathogen replicates well in hamsters or because the pathogenesis in these animals resembles that seen in human patients (Miao et al, 2019)

Summary

Introduction

Advancements have been made in the application of in vitro and in silico systems, the complexity of most diseases can be captured only in animal models. Hamsters have long been used in behavioral science, especially to study the effects of seasonal endocrinological changes and the circadian rhythm (De Lorme et al, 2013; Harris, 2017; Korf, 2018; Loudon et al, 2007) They are useful for research in the fields of reproductive biology (Hirose and Ogura, 2019) and epilepsy (Muñoz et al, 2017). Syrian hamsters are the only rodents that develop a clinical disease similar to hantavirus pulmonary syndrome, and SARS-CoV infection results in severe respiratory disease in immunosuppressed hamsters (Safronetz et al, 2012; Schaecher et al, 2008). Hamsters are a natural host for SARS-CoV-2, replicating the pathology and virus spread characteristics of the virus in human patients (Chan et al, 2020; Sia et al, 2020)

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