A safe and sensitive enterovirus A71 infection model based on human SCARB2 knock-in mice

Zhou, Shaoman; Liu, Qiang; Wu, Xing; Chen, Pan; Wu, Xi; Guo, Junming; Liu, Susu; Liang, Zhenglun; Fan, Chen; Wang, Youchun

doi:10.1016/j.vaccine.2016.04.029

Cited by 23 publications

(21 citation statements)

References 31 publications

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“…Here, to simplify this process of viral vector evaluation, we used BLI to monitor the dissemination of Adv5 and dynamically localize it in unexpected anatomical sites in the same animals by measuring the firefly luciferase expressed by Ad5-Fluc. We and others have also shown a significant correlation between photoemission and viral load in vivo and have demonstrated the many advantages of BLI, including the ability to image each animal repeatedly, which is both ethically and economically advantageous 19, 20 .…”

Section: Discussionmentioning

confidence: 86%

Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging

Liu

Zhou

Fan

et al. 2017

Sci Rep

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As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2 −/− animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2 −/− animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2 −/− mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-α and IFN-γ, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2 −/− mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2 −/− mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.

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Section: Discussionmentioning

confidence: 86%

Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging

Liu

Zhou

Fan

et al. 2017

Sci Rep

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“…An immunohistochemical analysis was performed with a monoclonal mouse anti-EBOVA antibody (clone M401, diluted 1:300; kindly provided by Sino Biological Inc., Beijing, China), as previously described38.…”

Section: Methodsmentioning

confidence: 99%

Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection

Liu

Fan

et al. 2017

Sci Rep

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Passive immunotherapy with monoclonal antibodies (mAbs) is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans. Understanding what constitutes a protective response is critical for the development of novel therapeutic strategies. We generated an EBOV-glycoprotein-pseudotyped Human immunodeficiency virus to develop sensitive neutralizing and antibody-dependent cellular cytotoxicity (ADCC) assays as well as a bioluminescent-imaging-based mouse infection model that does not require biosafety level 4 containment. The in vivo treatment efficiencies of three novel anti-EBOV mAbs at 12 h post-infection correlated with their in vitro anti-EBOV ADCC activities, without neutralizing activity. When they were treated with these mAbs, natural killer cell (NK)-deficient mice had lower viral clearance than WT mice, indicating that the anti-EBOV mechanism of the ADCC activity of these mAbs is predominantly mediated by NK cells. One potent anti-EBOV mAb (M318) displayed unprecedented neutralizing and ADCC activities (neutralization IC50, 0.018 μg/ml; ADCC EC50, 0.095 μg/ml). These results have important implications for the efficacy of antiviral drugs and vaccines as well as for pathogenicity studies of EBOV.

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“…However, tg mice older than 3 weeks were not susceptible to EV-A71, and the main EV-A71 replication site in the neonatal tg mice (unlike humans) was skeletal muscle. Zhou et al [68] generated SCARB2 knock-in mice in which SCARB2 cDNA driven by the CAG promoter was inserted into the ROSA26 locus. These knock-in mice were susceptible to EV-A71 infection.…”

Section: Scarb2mentioning

confidence: 99%

Cellular receptors for enterovirus A71

Kobayashi

Koike

2020

J Biomed Sci

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Enterovirus 71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease. EV-A71 infection is sometimes associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis, and cardiopulmonary failure. Therefore, EV-A71 is a serious public health concern. Scavenger receptor class B, member 2 (SCARB2) is a type III transmembrane protein that belongs to the CD36 family and is a major receptor for EV-A71. SCARB2 supports attachment and internalization of the virus and initiates conformational changes that lead to uncoating of viral RNA in the cytoplasm. The three-dimensional structure of the virus-receptor complex was elucidated by cryo-electron microscopy. Two α-helices in the head domain of SCARB2 bind to the G-H loop of VP1 and the E-F loop of VP2 capsid proteins of EV-A71. Uncoating takes place in a SCARB2-and low pH-dependent manner. In addition to SCARB2, other molecules support cell surface binding of EV-A71. Heparan sulfate proteoglycans, P-selectin glycoprotein ligand-1, sialylated glycan, annexin II, vimentin, fibronectin, and prohibitin enhance viral infection by retaining the virus on the cell surface. These molecules are known as "attachment receptors" because they cannot initiate uncoating. In vivo, SCARB2 expression was observed in EV-A71 antigenpositive neurons and epithelial cells in the crypts of the palatine tonsils in patients that died of EV-A71 infection. Adult mice are not susceptible to infection by EV-A71, but transgenic mice that express human SCARB2 become susceptible to EV-A71 infection and develop neurological diseases similar to those observed in humans. Attachment receptors may also be involved in EV-A71 infection in vivo. Although heparan sulfate proteoglycans are expressed by many cultured cell lines and enhance infection by a subset of EV-A71 strains, they are not expressed by cells that express SCARB2 at high levels in vivo. Thus, heparan sulfate-positive cells merely adsorb the virus and do not contribute to replication or dissemination of the virus in vivo. In addition to these attachment receptors, cyclophilin A and human tryptophanyl aminoacyl-tRNA synthetase act as an uncoating regulator and an entry mediator that can confer susceptibility to non-susceptibile cells in the absence of SCARB2, respectively. The roles of attachment receptors and other molecules in EV-A71 pathogenesis remain to be elucidated.

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A safe and sensitive enterovirus A71 infection model based on human SCARB2 knock-in mice

Cited by 23 publications

References 31 publications

Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging

Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging

Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection

Cellular receptors for enterovirus A71

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