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Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity

Cellular & Molecular Immunology volume 18, pages 472–483 (2021)Cite this article

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Abstract

Virus-induced asthma is prevalent among children, but its underlying mechanisms are unclear. Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma. Nonetheless, the relationship between systemic virus infections, such as enterovirus infection, and the ensuing effects on allergic asthma development is unknown. Early-life enterovirus infection was correlated with higher risks of allergic diseases in children. Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period. Bone marrow-derived macrophages (BMDMs) from recovered EV-A71-infected mice showed sustained innate immune memory (trained immunity) that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites. Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice, which was inhibited by 2-deoxy-D-glucose (2-DG) pretreatment, suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.

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Acknowledgements

We are grateful to S.H.C. and S.M.W. for providing EV-A71, incubation cell lines and experimental instructions for EV-A71 infection. This study was based, in part, on data from the NHIRD provided by the Bureau of National Health Insurance and Department of Health and managed by the National Health Research Institutes. The interpretation and conclusions herein do not represent those of the Bureau of National Health Insurance, Department of Health or National Health Research Institutes. This study was, in part, supported by the Centre of Allergy and Mucosal Immunity, Headquarters of University Advancement at the National Cheng Kung University, Ministry of Education, Taiwan. H.J.T is supported in part by a grant from the National Health Research Institutes (PI: Tsai, PH-101-PP-14, PH-101-SP-14, and PH-108-PP-08).

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  1. Jiu-Yao Wang

    Present address: Department of Pediatrics, National Cheng Kung University Hospital, No, 139, Sheng-Li Road, Tainan, 70428, Taiwan, China

Authors and Affiliations

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

    Pei-Chi Chen & Miao-Hsi Hsieh

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

    Yu-Ting Shao & Shun-Hua Chen

  3. Center for Allergy and Clinical Immunology Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, China

    Hui-Fang Kao, Wen-Shuo Kuo & Jiu-Yao Wang

  4. Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan, China

    Hui-Fang Kao

  5. School of Chemistry and Materials Science, Nanjing University of Information Science and Technology, Nanjing, China

    Wen-Shuo Kuo

  6. Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan, China

    Shih-Min Wang & Jiu-Yao Wang

  7. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, China

    Lawrence Shih Hsin Wu

  8. Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan, China

    Hui-Ju Tsai

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Contributions

P.C.C. and Y.T.S. designed the original model. S.H.C. and S.M.W. provided EV-A71, incubation cell lines, and experimental instructions for EV-A71 infection. P.C.C., Y.T.S., and M.H. designed and conducted all experiments with guidance from H.F.K., W.S.K., R.V., Z.G.L., and J.Y.W. The national health database analysis was conducted by H.J.T. L.S.H.W. fit the statistical models for the analysis of experimental data, and P.C.C., M.H.H., H.F.K., R.V., H.J.T., and J.Y.W. analyzed all the data, wrote the original manuscript, and prepared the final figures. H.J.T. and J.Y.W. secured funding for this project. J.Y.W. authored the final manuscript.

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Correspondence to Jiu-Yao Wang.

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Chen, PC., Shao, YT., Hsieh, MH. et al. Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity. Cell Mol Immunol 18, 472–483 (2021). https://doi.org/10.1038/s41423-020-00621-4

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