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Subneutralizing antibodies to enterovirus 71 induce antibody-dependent enhancement of infection in newborn mice

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Abstract

Antibody-dependent enhancement (ADE) of virus infections can be induced by subneutralizing concentrations of specific antibodies. We recently demonstrated ADE in human monocytes infected with enterovirus 71 (EV71). The current study was designed to extend these observations by determining the effect of ADE on the pathogenesis of EV71 infection in newborn mice. We compared the clinical manifestations, mortality, virus titer, histopathology, and serum levels of cytokines and chemokines in newborn mice pretreated with subneutralizing antibodies to EV71 or normal mouse IgG with and without virus. Seven-day-old ICR mice were pretreated with a wide range of mouse anti-EV71 IgG 24 h prior to intraperitoneal injection of EV71. Mice were protected from infection by neutralizing doses of anti-EV71 IgG ranging from 6.43 × 10−1 to 329.6 μg/ml. Subneutralizing doses ranging from 2.01 × 10−2 to 3.21 × 10−1 μg/ml were found to significantly increase 14-day mortality compared to virus alone. The ADE effect was not evident at lower doses. Histopathological examination of mice given a subneutralizing dose of 8.04 × 10−2 μg/ml revealed extensive neuronal and muscular damage compared to untreated infected controls. Higher serum levels of interferon (IFN)-γ and monocyte chemoattractant protein (MCP)-1 were noted in mice pretreated with subneutralizing doses than untreated infected controls. These findings support the concept that subneutralizing antibodies directed enhance EV71 induce ADE in newborn mice.

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Acknowledgments

The authors thank Dr. Calvin M. Kunin for providing invaluable suggestions and a critical review of the manuscript. This study was supported by grants from National Science Council, Taiwan (96-2314-B-006-033-MY2 and 98-2314-B-006-002-MY3), Department of Health, Executive Yuan, Taiwan (DOH101-TD-B-111-102), and Center of Infectious Disease and Signaling Research, National Cheng Kung University, Taiwan.

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Authors and Affiliations

  1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    I-Chun Chen

  2. Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70428, Taiwan

    Shih-Min Wang

  3. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Chun-Keung Yu

  4. Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70428, Taiwan

    Ching-Chuan Liu

  5. Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

    Shih-Min Wang, Chun-Keung Yu & Ching-Chuan Liu

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  1. I-Chun Chen
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  2. Shih-Min Wang
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Correspondence to Shih-Min Wang or Ching-Chuan Liu.

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Chen, IC., Wang, SM., Yu, CK. et al. Subneutralizing antibodies to enterovirus 71 induce antibody-dependent enhancement of infection in newborn mice. Med Microbiol Immunol 202, 259–265 (2013). https://doi.org/10.1007/s00430-013-0289-y

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  • DOI: https://doi.org/10.1007/s00430-013-0289-y

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