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

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

doi:10.1038/srep31151

Cited by 28 publications

(35 citation statements)

References 31 publications

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“…This model was able to support efficient lower titer (1 million pfu/mouse) EV71 experimental infection using older mice. Therefore, this hybrid model lends a strong support to the importance of both entry factor and host innate immunity ( Liou et al, 2016 ).…”

Section: Deciphering Pathophysiology Using In Vitro mentioning

confidence: 74%

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

et al. 2017

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Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. Infection can cause severe neurological, cardiac, and respiratory problems in children under the age of 5. Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host–viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions.

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Section: Deciphering Pathophysiology Using In Vitro mentioning

confidence: 74%

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

et al. 2017

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“…Additionally, Liou et al derived a transgenic mouse that expresses hSCARB2 under the control of a SCARB2 promoter. The neonates of this transgenic line displayed low susceptibility to intraperitoneal viral inoculation (41). Furthermore, Fujii et al used a human SCARB2 gene-containing BAC to establish a transgenic mouse, which could be effectively infected with the Isehara strain via the i.c., i.v., and i.p.…”

Section: Discussionmentioning

confidence: 99%

A Novel Murine Model Expressing a Chimeric mSCARB2/hSCARB2 Receptor Is Highly Susceptible to Oral Infection with Clinical Isolates of Enterovirus 71

Yang

Liang²,

Jiang

et al. 2019

J Virol

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Enterovirus 71 (EV71) infection is generally associated with hand-footand-mouth disease (HFMD) and may cause severe neurological disorders and even death. An effective murine oral infection model for studying the pathogenesis of various clinical EV71 isolates is lacking. We developed a transgenic (Tg) mouse that expresses an EV71 receptor, that is, human scavenger receptor class B member 2 (hSCARB2), in a pattern highly similar to that of endogenous murine SCARB2 (mSCARB2) protein. A FLAG-tagged SCARB2 cDNA fragment composed of exons 3 to 12 was inserted into a murine Scarb2 gene-containing bacterial artificial chromosome (BAC) clone, and the resulting transgene was used for establishment of chimeric receptor-expressing Tg mice. Tg mice intragastrically (i.g.) infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia and paralysis, and fatality. There was an age-dependent decrease in susceptibility to viral infection. Pathological characteristics of the infected Tg mice resembled those of encephalomyelitis in human patients. Viral infection was accompanied by microglial activation. Clodronate treatment of the brain slices from Tg mice enhanced viral replication, while lipopolysaccharide treatment significantly inhibited it, suggesting an antiviral role for microglia during EV71 infection. Taken together, this Tg mouse provides a model that closely mimics natural infection for studying EV71 pathogenesis and for evaluating the efficacy of vaccines or other antiviral drugs. IMPORTANCE The availability of a murine model of EV71 infection is beneficial for the understanding of pathogenic mechanisms and the development and assessment of vaccines and antiviral drugs. However, the lack of a murine oral infection model thwarted the study of pathogenesis induced by clinically relevant EV71 strains that are transmitted via the oral-oral or oral-fecal route. Our Tg mice could be intragastrically infected with clinically relevant EV71 strains in an efficient way and developed neurological symptoms and pathological changes strikingly resembling those of human infection. Moreover, these mice showed an age-dependent change in susceptibility that is similar to the human case. This Tg mouse, when combined with the use of other genetically modified mice, potentially contributes to studying the relationship between developmental changes in immunity and susceptibility to virus.

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“…In their model, B genotypes of clinically isolated EV-A71 led to HFMD-like diseases while C genotypes led to neuropathogenesis, such as limb paralysis (LP). Another hybrid (hSCARB2+/+/stat-1−/−) mouse strain established from crossbreeding SCARB2 transgenic and stat-1 knockout (KO) mice was also susceptible to EV-A71 infection up to 2 weeks of age 23 . In the murine model developed by Fujii et al, young hSCARB2 Tg mice (3-week-old) were susceptible to infection by the EV-A71 Isehara strain (C genotype) and displayed features of neuropathology 19 .…”

Section: Introductionmentioning

confidence: 99%

Severity of enterovirus A71 infection in a human SCARB2 knock-in mouse model is dependent on infectious strain and route

Zhu

Chen

Zhou

et al. 2018

Emerging Microbes & Infections

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Enterovirus A71 (EV-A71) is a major etiological agent of human hand, foot and mouth disease, and it can cause severe neurological complications. Although several genotypes of EV-A71 strains are prevalent in different regions of the world, the genotype C4 has circulated in mainland China for more than 20 years. The pathogenicity of different EV-A71 clinical isolates varies and needs to be explored. In this study, hSCARB2 knock-in mice (N = 181) with a wide range of ages were tested for their susceptibility to two EV-A71 strains with the subgenotypes C4 and C2, and two infection routes (intracranial and venous) were compared. The clinical manifestations and pathology and their relationship to the measured viral loads in different tissues were monitored. We observed that 3 weeks is a crucial age, as mice younger than 3-week-old that were infected became extremely ill. However, mice older than 3 weeks displayed diverse clinical symptoms. Significant differences were observed in the pathogenicity of the two strains with respect to clinical signs, disease incidence, survival rate, and body weight change. We concluded that hSCARB2 knock-in mice are a sensitive model for investigating the clinical outcomes resulting from infection by different EV-A71 strains. The intracranial infection model appears to be suitable for evaluating EV-A71 neurovirulence, whereas the venous infection model is appropriate for studying the pathogenicity of EV-A71.

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

Cited by 28 publications

References 31 publications

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

A Novel Murine Model Expressing a Chimeric mSCARB2/hSCARB2 Receptor Is Highly Susceptible to Oral Infection with Clinical Isolates of Enterovirus 71

Severity of enterovirus A71 infection in a human SCARB2 knock-in mouse model is dependent on infectious strain and route

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