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


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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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).

Author information




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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The authors declare no competing interests.

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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).

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  • trained immunity
  • allergy
  • asthma


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