Human SCARB2 Transgenic Mice as an Infectious Animal Model for Enterovirus 71

Lin, Yi Wen; Yu, Shu; Shao, Hsiao Yun; Lin, Hsiang Yin; Liu, Chia-Chyi; Hsiao, Kuang Nan; Chitra, Ebenezer; Tsou, Yueh Liang; Chang, Hsuen Wen; Sia, Charles; Chong, Pele; Chow, Yen‐Hung

doi:10.1371/journal.pone.0057591

Cited by 90 publications

(143 citation statements)

References 52 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…Alternatively, immunodeficient mice (29,30) and transgenic mice with a human EV71 receptor (31,32) were found to be vulnerable to EV71 infection. The AG129 mouse is immunodeficient and without alpha/beta and gamma interferon (IFN) receptors; it can be infected by the non-mouse-adapted EV71 strain 41 (EV71-B4 in this paper, where B4 indicates the subgenogroup) (30).…”

mentioning

confidence: 99%

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Meng

Kwang

2014

J Virol

View full text Add to dashboard Cite

In a screen for ribavirin resistance, a novel high-fidelity variant of human enterovirus 71 (EV71) with the single amino acid change L123F in its RNA-dependent RNA polymerase (RdRp or 3D) was identified. Based on the crystal structure of EV71 RdRp, L123 locates at the entrance of the RNA template binding channel, which might form a fidelity checkpoint. EV71 RdRp-L123F variants generated less progeny in a guanidine resistance assay and virus populations with lower mutation frequencies in cell culture passage due to their higher replication fidelity. However, compared with wild-type viruses, they did not show growth defects. In vivo infections further revealed that high-fidelity mutations L123F and G64R (previously reported) negatively impacted EV71 fitness and greatly reduced viral pathogenicity alone or together in AG129 mice. Interestingly, a variant with double mutations, RG/B4-G64R/L123F (where RG/B4 is an EV71 genotype B4 virus constructed by reverse genetics [RG])showed higher fidelity in vitro and less virulence in vivo than any one of the above two single mutants. The 50% lethal dose (LD 50 ) of the double mutant increased more than 500 times compared with the LD 50 of wild-type RG/B4 in mice. The results indicated that these high-fidelity variants exhibited an attenuated pathogenic phenotype in vivo and offer promise as a live attenuated EV71 vaccine. IMPORTANCEThe error-prone nature of the RNA-dependent RNA polymerase (RdRp) of RNA viruses during replication results in quasispecies and aids survival of virus populations under a wide range of selective pressures. Virus variants with higher replication fidelity exhibit lower genetic diversity and attenuated pathogenicity in vivo. Here, we identified a novel high-fidelity mutation L123F in the RdRp of human enterovirus 71 (EV71). We further elucidated that EV71 variants with the RdRp-L123F mutation and/or the previously identified high-fidelity mutation RdRp-G64R were attenuated in an AG129 mouse model. As EV71 has emerged as a serious worldwide health threat, especially in developing countries in the Asia-Pacific region, we urgently need EV71 vaccines. Learning from the poliovirus vaccination, we prefer live attenuated EV71 vaccines to inactivated EV71 vaccines in order to effectively control EV71 outbreaks at low cost. Our results imply a new means of attenuating EV71 and reducing its mutation rate at the same time.

show abstract

mentioning

confidence: 99%

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Meng

Kwang

2014

J Virol

View full text Add to dashboard Cite

show abstract

“…Similarly, Nishimura et al (15) reported that human P-selectin glycoprotein ligand-1(PSGL-1) can also facilitate EV71 infection in vitro. Recently, it was reported that human SCARB2 (hSCARB2) transgenic (Tg) mice can serve as an animal model of EV71 infection (16,17). While these receptor Tg mice can suffer limb paralysis upon i.p.…”

mentioning

confidence: 99%

Immunodeficient Mouse Models with Different Disease Profiles byIn VivoInfection with the Same Clinical Isolate of Enterovirus 71

Liao

Liou

Chang

et al. 2014

J Virol

View full text Add to dashboard Cite

Like poliovirus infection, severe infection with enterovirus 71 (EV71) can cause neuropathology. Unlike poliovirus, EV71 is often associated with hand-foot-and-mouth disease (HFMD). Here we established three mouse models for experimental infection with the same clinical isolate of EV71. The NOD/SCID mouse model is unique for the development of skin rash, an HFMD-like symptom. While the NOD/SCID mice developed limb paralysis and death at near-100% efficiency, the gamma interferon receptor knockout (ifngr KO) and stat-1 knockout mice exhibited paralysis and death rates near 78% and 30%, respectively. Productive infection with EV71 depends on the viral dose, host age, and inoculation route. Levels of infectious EV71, and levels of VP1-specific RNA and protein in muscle, brain, and spinal cord, were compared side by side between the NOD/SCID and stat-1 knockout models before, during, and after disease onset. Spleen fibrosis and muscle degeneration are common in the NOD/SCID and stat-1 knockout models. The main differences between these two models include their disease manifestations and cytokine/ chemokine profiles. The pathology of the NOD/SCID model includes (i) inflammation and expression of viral VP1 antigen in muscle, (ii) increased neutrophil levels and decreased eosinophil and lymphocyte levels, and (iii) hair loss and skin rash. The characteristic pathology of the stat-1 knockout model includes (i) a strong tropism of EV71 for the central nervous system, (ii) detection of VP1 protein in the Purkinje layer of cerebellar cortex, pons, brain stem, and spinal cord, (iii) amplification of microglial cells, and (iv) dystrophy of intestinal villi. Our comparative studies on these new models with oral or intraperitoneal (i.p.) infection underscored the contribution of host immunity, including the gamma interferon receptor, to EV71 pathogenesis. IMPORTANCEIn the past decade, enterovirus 71 (EV71) has emerged as a major threat to public health in the Asia-Pacific region. Disease manifestations include subclinical infection, common-cold-like syndromes, hand-foot-and-mouth disease (HFMD), uncomplicated brain stem encephalitis, severe dysregulation of the autonomic nerve system, fatal pulmonary edema, and cardiopulmonary collapse. To date, no effective vaccine or treatment is available. A user-friendly and widely accessible animal model for researching EV71 infection and pathogenesis is urgently needed by the global community, both in academia and in industry.

show abstract

“…In addition, it will be necessary to establish a scientific basis for this potential therapeutic role of GBA1 by conducting experiments in mouse models, e.g. assessing the ability of Cerezyme to control EV71 infection in vivo, although the relevance of small animal models to the pathology of EV71 in humans is still controversial [11,15].…”

Section: Discussionmentioning

confidence: 99%

“…In 2009, researchers reported the discovery of two EV71 receptors, i.e. human scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2) or CD36b like-2; and P-selectin glycoprotein ligand-1 (PSGL-1), also known as CD162 [9][10][11]. SCARB2 is expressed in most cell types, whereas PSGL-1 is limited to blood cells and endothelial cells, suggesting a distinct role for these two receptors in the pathogenesis of EV71 infection in vivo [12].…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Nakata

Takeda

Tanaka

et al. 2017

Journal of General Virology

View full text Add to dashboard Cite

Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD). EV71 causes fever, rash, diarrhoea and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid b-glucosidase 1 (GBA1; also known as bglucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease and having recombinant human GBA1 as the active ingredient, protected against EV71 infection. The anti-EV71 activity of GBA1 was bimodal: endogenous GBA1 restricted cell surface expression levels of scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2), and exogenous recombinant GBA1 interfered with EV71 to interact with SCARB2 outside the cell. Thus, our findings suggest that GBA1 may represent a novel molecular target for the treatment of EV71 infection.

show abstract

Human SCARB2 Transgenic Mice as an Infectious Animal Model for Enterovirus 71

Cited by 90 publications

References 52 publications

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Immunodeficient Mouse Models with Different Disease Profiles byIn VivoInfection with the Same Clinical Isolate of Enterovirus 71

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Contact Info

Product

Resources

About