Dirty Fish Versus Squeaky Clean Mice: Dissecting Interspecies Differences Between Animal Models of Interferonopathy.

Holly A Rutherford,Noémie Hamilton,Paul R Kasher

doi:10.3389/fimmu.2020.623650

Abstract

Autoimmune and autoinflammatory diseases are rare but often devastating disorders, underpinned by abnormal immune function. While some autoimmune disorders are thought to be triggered by a burden of infection throughout life, others are thought to be genetic in origin. Among these heritable disorders are the type I interferonopathies, including the rare Mendelian childhood-onset encephalitis Aicardi-Goutières syndrome. Patients with Aicardi Goutières syndrome are born with defects in enzymes responsible for nucleic acid metabolism and develop devastating white matter abnormalities resembling congenital cytomegalovirus brain infection. In some cases, common infections preceded the onset of the disease, suggesting immune stimulation as a potential trigger. Thus, the antiviral immune response has been actively studied in an attempt to provide clues on the pathological mechanisms and inform on the development of therapies. Animal models have been fundamental in deciphering biological mechanisms in human health and disease. Multiple rodent and zebrafish models are available to study type I interferonopathies, which have advanced our understanding of the human disease by identifying key pathological pathways and cellular drivers. However, striking differences in phenotype have also emerged between these vertebrate models, with zebrafish models recapitulating key features of the human neuropathology often lacking in rodents. In this review, we compare rodent and zebrafish models, and summarize how they have advanced our understanding of the pathological mechanisms in Aicardi Goutières syndrome and similar disorders. We highlight recent discoveries on the impact of laboratory environments on immune stimulation and how this may inform the differences in pathological severity between mouse and zebrafish models of type I interferonopathies. Understanding how these differences arise will inform the improvement of animal disease modeling to accelerate progress in the development of therapies for these devastating childhood disorders.

Highlights

Type I interferons (IFNs) play an essential role in the antiviral innate immune response—protecting the host from productive viral infection before the development of adaptive immune response to pathogens [1, 2]
The vastly different phenotypes between zebrafish and rodent models with mutations of the same gene highlight the importance of model choice, methodological considerations and, perhaps most importantly, pathogen exposure when modeling disorders of the immune system
All authors contributed to the article and approved the submitted version

Summary

Introduction

Type I interferons (IFNs) play an essential role in the antiviral innate immune response—protecting the host from productive viral infection before the development of adaptive immune response to pathogens [1, 2]. The vastly different phenotypes between zebrafish and rodent models with mutations of the same gene highlight the importance of model choice, methodological considerations and, perhaps most importantly, pathogen exposure when modeling disorders of the immune system.

Results

Conclusion