A new animal model containing human SCARB2 and lacking stat-1 is highly susceptible to EV71.

An-Ting Liou,Chih-Shin Chang,Chun-Che Liao,Szu-Yao Wu,Ya-Shu Chang,Chiaho Shih

doi:10.1038/srep31151

Abstract

Enterovirus 71 (EV71) is a major threat to children worldwide. Children infected with EV71 could develop subclinical infection and hand-foot-and -mouth disease (HFMD). In severe cases, patients could develop encephalitis, paralysis, pulmonary edema, and death. A more user-friendly and robust animal model is essential to investigating EV71 pathogenesis. Here, we established a hybrid (hSCARB2+/+/stat-1−/−) mouse strain from crossbreeding SCARB2 transgenic and stat-1 KO mice, and compared the susceptibilities to EV71 infection and pathogenesis between parental and hybrid mice. Virus-encoded VP1 protein can be detected in the streaking nerve fibers in brain and spinal cord. This hybrid mouse strain at 2-week-old age can still be infected with different genotypes of EV71 at 1000-fold lower titer via an ip route. Infected hybrid mice developed earlier onset of CNS disease, paralysis, and death at a higher incidence. These advantages of this novel model meet the urgent need from the scientific community in basic and preclinical research in therapeutics and pathogenesis.

Highlights

Rather resistant to Enterovirus 71 (EV71) infection and pathogenesis
The weak signal in stat-1−/− mice is from the endogenous mouse SCARB2 protein, which can cross-react with the anti-SCARB2 antibody.In contrast, we detected no apparent difference in SCARB2 protein expression in spleen and muscle, which could be due to the low level expression of the exogenous Human SCARB2 (hSCARB2) driven by the native promoter of hSCARB2 in spleen and muscle
In our hSCARB2 transgenic model and the stat-1 KO model, mouse age younger than 1-week old is necessary for successful EV71 infection and pathogenesis

Summary

Introduction

Rather resistant to EV71 infection and pathogenesis. Currently, there is no data available to side-by-side cross compare the phenotypes and susceptibility of various hSCARB2 Tg mouse models to EV71 infection. Immunodeficient mouse models without bearing a hSCARB2 transgene, such as AG129, G129, NOD/SCID, and stat-1 KO (stat-1−/−) mice, can support efficient in vivo infection with EV7119–21. The NOD/ SCID model is deficient in both B and T cell maturation[24] Overall, both adaptive and innate immunity are important against EV71 infection. Neuropathology and microglial amplification are evident by Nissl’s staining and immunohistochemistry (IHC) for IBA1, an inflammation marker of microglial cells These hybrid mice tend to develop an earlier onset of limb paralysis and death. Taken together, both hSCARB2 receptor and innate immunity are important determinants for EV71 infection and pathogenesis. A striking synergistic effect from hSCARB2 and the deficiency in innate immunity enables in vivo infection with different genotypes of EV71 at a 2-3 log lower dose of viral inoculation

Methods

Results

Conclusion