Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Boonpiyathad, T., Sozener, Z. C., Satitsuksanoa, P., & Akdis, C. A. Immunologic mechanisms in asthma. Semin. Immunol. 46, 101333 (2019) https://doi.org/10.1016/j.smim.2019.101333.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Jackson, D. J., Gern, J. E. & Lemanske, R. F. Jr. Lessons learned from birth cohort studies conducted in diverse environments. J. Allergy Clin. Immunol. 139, 379–386 (2017).

    Article  PubMed Central  Google Scholar 

  3. 3.

    Custovic, A. et al. Cytokine responses to rhinovirus and development of asthma, allergic sensitization, and respiratory infections during childhood. Am. J. Respir. Crit. Care Med. 197, 1265–1274 (2018).

    CAS  Article  PubMed Central  Google Scholar 

  4. 4.

    Lukkarinen, M. & Jartti, T. The first rhinovirus-wheeze acts as a marker for later asthma in high-risk children. J. Allergy Clin. Immunol. 138, 313 (2016).

    Article  Google Scholar 

  5. 5.

    Su, Y. T. et al. High correlation between human rhinovirus type C and children with asthma exacerbations in Taiwan. J. Microbiol. Immunol. Infect. 53, 561–568 (2020) https://doi.org/10.1016/j.jmii.2018.12.001.

    Article  PubMed  Google Scholar 

  6. 6.

    Shi, T. et al. Association between respiratory syncytial virus-associated acute lower respiratory infection in early life and recurrent wheeze and asthma in later childhood. J. Infect. Dis. 222, S628–S633 (2020).

    Article  Google Scholar 

  7. 7.

    Farne, H. A. & Johnston, S. L. Immune mechanisms of respiratory viral infections in asthma. Curr. Opin. Immunol. 48, 31–37 (2017).

    CAS  Article  Google Scholar 

  8. 8.

    Kumar, R. K., Foster, P. S. & Rosenberg, H. F. Respiratory viral infection, epithelial cytokines, and innate lymphoid cells in asthma exacerbations. J. Leukoc. Biol. 96, 391–396 (2014).

    Article  PubMed Central  Google Scholar 

  9. 9.

    Byrne, A. J., Mathie, S. A., Gregory, L. G. & Lloyd, C. M. Pulmonary macrophages: key players in the innate defence of the airways. Thorax 70, 1189–1196 (2015).

    Article  PubMed Central  Google Scholar 

  10. 10.

    Huang, C. C. et al. Neurologic complications in children with enterovirus 71 infection. N. Engl. J. Med. 341, 936–942 (1999).

    CAS  Article  Google Scholar 

  11. 11.

    Lee, Z. M., Huang, Y. H., Ho, S. C. & Kuo, H. C. Correlation of symptomatic enterovirus infection and later risk of allergic diseases via a population-based cohort study. Medicine 96, e5827 (2017).

    Article  PubMed Central  Google Scholar 

  12. 12.

    Yeh, J. J., Lin, C. L. & Hsu, W. H. Effect of enterovirus infections on asthma in young children: a national cohort study. Eur. J. Clin. Invest. 47, 12 (2017).

    Article  Google Scholar 

  13. 13.

    Wang, Y. C. et al. Association between enterovirus infection and asthma in children: a 16-year nationwide population-based cohort study. Pediatr. Infect. Dis. J. 37, 844–849 (2018).

    Article  Google Scholar 

  14. 14.

    Netea, M. G., Latz, E., Mills, K. H. & O’Neill, L. A. Innate immune memory: a paradigm shift in understanding host defense. Nat. Immunol. 16, 675–679 (2015).

    CAS  Article  Google Scholar 

  15. 15.

    Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science. 352, aaf1098 (2016) https://doi.org/10.1126/science.aaf1098

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Włodarczyk, M., Druszczyńska, M. & Fol, M. Trained innate immunity not always amicable. Inter. J. Mol. Sci. 20, 10 (2019).

    Google Scholar 

  17. 17.

    Huang, S. W. et al. Exogenous interleukin-6, interleukin-13, and interferon-γ provoke pulmonary abnormality with mild edema in enterovirus 71-infected mice. Respir. Res. 12, 147 (2011).

    CAS  Article  PubMed Central  Google Scholar 

  18. 18.

    Shen, F. H., Shen, T. J., Chang, T. M., Su, I. J. & Chen, S. H. Early dexamethasone treatment exacerbates enterovirus 71 infection in mice. Virology 464-465, 218–227 (2014).

    CAS  Article  Google Scholar 

  19. 19.

    Siegle, J. S. et al. Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice. Respir. Res. 11, 14 (2010).

    Article  PubMed Central  Google Scholar 

  20. 20.

    Blomqvist, S., Savolainen, C., Råman, L., Roivainen, M. & Hovi, T. Human rhinovirus 87 and enterovirus 68 represent a unique serotype with rhinovirus and enterovirus features. J. Clin. Microbiol. 40, 4218–4223 (2002).

    Article  PubMed Central  Google Scholar 

  21. 21.

    Wang, S. M. et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J. Infect. Dis. 188, 564–570 (2003).

    CAS  Article  PubMed Central  Google Scholar 

  22. 22.

    Edwards, M. R. et al. Viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness. J. Allergy Clin. Immunol. 140, 909–920 (2017).

    CAS  Article  PubMed Central  Google Scholar 

  23. 23.

    Jartti, T. & Gern, J. E. Role of viral infections in the development and exacerbation of asthma in children. J. Allergy Clin. Immunol. 140, 895–906 (2017).

    Article  PubMed Central  Google Scholar 

  24. 24.

    Cormier, S. A., You, D. & Honnegowda, S. The use of a neonatal mouse model to study respiratory syncytial virus infections. Expert Rev. Anti Infect. Ther. 8, 1371–1380 (2010).

    Article  PubMed Central  Google Scholar 

  25. 25.

    Schneider, D. et al. Neonatal rhinovirus infection induces mucous metaplasia and airways hyperresponsiveness. J. Immunol. 188, 2894–2904 (2012).

    CAS  Article  PubMed Central  Google Scholar 

  26. 26.

    Al-Garawi, A. et al. Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood. Mucosal Immunol. 4, 682–694 (2011).

    CAS  Article  PubMed Central  Google Scholar 

  27. 27.

    Pali-Scholl, I. & Jensen-Jarolim, E. The concept of allergen-associated molecular patterns (AAMP). Curr. Opin. Immunol. 42, 113–118 (2016).

    Article  PubMed Central  Google Scholar 

  28. 28.

    Keegan, A. D. et al. Enhanced allergic responsiveness after early childhood infection with respiratory viruses: Are long-lived alternatively activated macrophages the missing link? Pathog. Dis. 74, 5 (2016).

    Article  Google Scholar 

  29. 29.

    Saradna, A., Do, D. C., Kumar, S., Fu, Q. L. & Gao, P. Macrophage polarization and allergic asthma. Transl. Res. 191, 1–14 (2018).

    CAS  Article  PubMed Central  Google Scholar 

  30. 30.

    Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e119 (2018).

    CAS  Article  Google Scholar 

  31. 31.

    Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e112 (2018).

    CAS  Article  PubMed Central  Google Scholar 

  32. 32.

    Machiels, B. et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650 (2018).

    CAS  Article  Google Scholar 

  34. 34.

    Halim, T. Y. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17, 57–64 (2016).

    CAS  Article  Google Scholar 

  35. 35.

    Sanchez-Ramon, S. et al. Trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations. Front. Immunol. 9, 2936 (2018).

    CAS  Article  PubMed Central  Google Scholar 

  36. 36.

    Marra, F. et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 123, 1003–1010 (2009).

    Article  Google Scholar 

  37. 37.

    Suh, D. C. et al. Economic burden of atopic manifestations in patients with atopic dermatitis–analysis of administrative claims. J. Manag. Care Pharm. 13, 778–789 (2007).

    Article  Google Scholar 

  38. 38.

    Hankin, C. S. et al. Allergy immunotherapy among Medicaid-enrolled children with allergic rhinitis: patterns of care, resource use, and costs. J. Allergy Clin. Immunol. 121, 227–232 (2008).

    Article  Google Scholar 

  39. 39.

    Cheng, S. C. et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    Article  PubMed Central  Google Scholar 

  40. 40.

    Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562–2571 (2016).

    CAS  Article  PubMed Central  Google Scholar 

  41. 41.

    Capote, J. et al. Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype. J. Cell Biol. 213, 275–288 (2016).

    CAS  Article  PubMed Central  Google Scholar 

  42. 42.

    Carlson, S. et al. Cardiac macrophages adopt profibrotic/M2 phenotype in infarcted hearts: role of urokinase plasminogen activator. J. Mol. Cell Cardiol. 108, 42–49 (2017).

    CAS  Article  PubMed Central  Google Scholar 

Download references

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).

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Jiu-Yao Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • trained immunity
  • allergy
  • asthma

Search

Quick links