Protective Efficacy of VP1-Specific Neutralizing Antibody Associated with a Reduction of Viral Load and Pro-Inflammatory Cytokines in Human SCARB2-Transgenic Mice

Hsuen-Wen Chang,Charles Sia,Pele Chong,Chia-Chyi Liu,Yen-Hung Chow,Hui-Min Ho,Hsiao-Yun Shao,Yi-Wen Lin,Min-Han Lin,Helene F Rosenberg

doi:10.1371/journal.pone.0069858

Hsuen-Wen Chang, Charles Sia + Show 8 more

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https://doi.org/10.1371/journal.pone.0069858

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Abstract

Hand-foot-mouth diseases (HFMD) caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16) in children have now become a severe public health issue in the Asian-Pacific region. Recently we have successfully developed transgenic mice expressing human scavenger receptor class B member 2 (hSCARB2, a receptor of EV71 and CVA16) as an animal model for evaluating the pathogenesis of enterovirus infections. In this study, hSCARB2-transgenic mice were used to investigate the efficacy conferred by a previously described EV71 neutralizing antibody, N3. A single injection of N3 effectively inhibited the HFMD-like skin scurfs in mice pre-infected with clinical isolate of EV71 E59 (B4 genotype) or prevented severe limb paralysis and death in mice pre-inoculated with 5746 (C2 genotype). This protection was correlated with remarkable reduction of viral loads in the brain, spinal cord and limb muscles. Accumulated viral loads and the associated pro-inflammatory cytokines were all reduced. The protective efficacy of N3 was not observed in animals challenged with CVA16. This could be due to dissimilarity sequences of the neutralizing epitope found in CVA16. These results indicate N3 could be useful in treating severe EV71 infections and the hSCARB2-transgenic mouse could be used to evaluate the protective efficacy of potential anti-enterovirus agent candidates.

Highlights

Enterovirus 71 (EV71) is a positive single-stranded RNA virus belonging to the Picornavirudae family
We investigate whether the hSCARB2-transgenic mouse model could be suitable for evaluating the protective efficacy conferred by a previously described enterovirus 71 (EV71)-specific neutralizing antibody, N3 [17]
To further investigate the protective efficacy of N3 antibodies against EV71 infection in vivo, 1-day old hSCARB2-transgenic mice were preinfected with 16107 pfu of E59 subcutaneously (s.c.) followed by administration of N3 or isotype antibody (200 mg) i.p. for 3 h post infection

Summary

Introduction

Enterovirus 71 (EV71) is a positive single-stranded RNA virus belonging to the Picornavirudae family. EV71 together with Coxsackievirus 16 (CVA16), CVA5, and CVA10, are known to be major causative agents that cause mild rash symptoms called hand-foot-and-mouth disease (HFMD) in infants and children [1]. Anti-EV71 viral drugs and vaccine are being developed, but their protective efficacy could not be efficiently evaluated due to lack of proper animal model. Several animal models have been developed to be EV71 infectious model using the mouse-adapted strain of EV71 [5], innate immunodeficient mice [6], or monkey models [7]. The intraperitoneal (i.p.) injection of clinical isolate of EV71 to adult mice caused no apparent clinical symptoms.

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