Article

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

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Abstract

Enterovirus (EV) 71 infection has been widely acknowledged as the leading cause of severe hand, foot and mouth disease (HFMD), which may rapidly lead to fatal pulmonary edema. In this study, we established a mouse model for EV71 infection exhibiting high incidence of severe symptoms with pulmonary edema. Mast cells (MCs) accumulation, activation and allergic inflammation were found in the brains, lungs and skeletal muscle of mice after EV71 infection, especially in the lungs of mice. Levels of histamine, platelet-activating factor (PAF), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), nitric oxide (NO), endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and noradrenaline (NA) were increased in EV71-infected lungs. In addition, EV71 infection reduced the number of pulmonary T cells, dendritic cells (DCs) and monocytes, and increased the number of lung eosinophils, Tregs and MCs. MCs number and tryptase expression in target organs or tissues posed a trend towards an increase from control to severe mice. There were positive correlations between MCs number in the brains (r = 0.701, P = 0.003), lungs (r = 0.802, P < 0.0001), skeletal muscles (r = 0.737, P = 0.001) and mean clinical score. Thus, our results suggested that MCs contributed to the pulmonary edema during EV71 infection.

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References

  1. 1.

    Duan G, Yang H, Shi L, et al. Serum inflammatory cytokine levels correlate with hand-foot-mouth disease severity: a nested serial case-control study. PLoS ONE. 2014;9:e112676.

  2. 2.

    Solomon T, Lewthwaite P, Perera D, et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10:778–90.

  3. 3.

    Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929–35.

  4. 4.

    Lum LC, Wong KT, Lam SK, et al. Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis. Lancet. 1998;352:1391.

  5. 5.

    Ooi MH, Wong SC, Lewthwaite P, et al. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010;9:1097–105.

  6. 6.

    Rivera A, Siracusa MC, Yap GS, et al. Innate cell communication kick-starts pathogen-specific immunity. Nat Immunol. 2016;17:356–63.

  7. 7.

    Pathinayake PS, Hsu AC, Wark PA. Innate Immunity and Immune Evasion by Enterovirus 71. Viruses. 2015;7:6613–30.

  8. 8.

    Liu Y, Zhu M, Nishida K, et al. An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. J Exp Med. 2007;204:93–103.

  9. 9.

    Urb M, Sheppard DC. The role of mast cells in the defence against pathogens. PLoS Pathog. 2012;8:e1002619.

  10. 10.

    Abraham SN, St, John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10:440–52.

  11. 11.

    McLeod JJ, Baker B, Ryan JJ. Mast cell production and response to IL-4 and IL-13. Cytokine. 2015;75:57–61.

  12. 12.

    Wilgus TA, Wulff BC. The importance of mast cells in dermal scarring. Adv Wound Care. 2014;3:356–65.

  13. 13.

    Amin K. The role of mast cells in allergic inflammation. Respir Med. 2012;106:9–14.

  14. 14.

    Yamaya M. Virus infection-induced bronchial asthma exacerbation. Pulm Med. 2012;2012:834826.

  15. 15.

    Smith-Norowitz TA, Carvajal-Raga S, Weedon J, et al. Increased seroprevalence of Enterovirus 71 IgE antibodies in asthmatic compared with non-asthmatic children. Ir J Med Sci. 2017;186:495–503.

  16. 16.

    Lee ZM, Huang YH, Ho SC, et al. Correlation of symptomatic enterovirus infection and later risk of allergic diseases via a population-based cohort study. Medicine (Baltim). 2017;96:e5827.

  17. 17.

    Dang D, Zhang C, Zhang R, et al. Involvement of inducible nitric oxide synthase and mitochondrial dysfunction in the pathogenesis of enterovirus 71 infection. Oncotarget. 2017;8:81014–26.

  18. 18.

    Liu CC, Lian WC, Butler M, et al. High immunogenic enterovirus 71 strain and its production using serum-free microcarrier Vero cell culture. Vaccine. 2007;25:19–24.

  19. 19.

    Wang YF, Chou CT, Lei HY, et al. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol. 2004;78:7916–24.

  20. 20.

    Thurlbeck WM. Internal surface area and other measurements in emphysema. Thorax. 1967;22:483–96.

  21. 21.

    Mizutani N, Nabe T, Yoshino S. Complement C3a regulates late asthmatic response and airway hyperresponsiveness in mice. J Immunol. 2009;183:4039–46.

  22. 22.

    Zarnegar B, Mendez-Enriquez E, Westin A, et al. Influenza infection in mice induces accumulation of lung mast cells through the recruitment and maturation of mast cell progenitors. Front Immunol. 2017;8:310.

  23. 23.

    Li H, Li Q, Du X, et al. Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells. J Cereb Blood Flow Metab. 2011;31:2106–15.

  24. 24.

    Huang PN, Shih SR. Update on enterovirus 71 infection. Curr Opin Virol. 2014;5:98–104.

  25. 25.

    Chang LY, Huang YC, Lin TY. Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet. 1998;352:367–8.

  26. 26.

    Khong WX, Yan B, Yeo H, et al. A non-mouse-adapted enterovirus 71 (EV71) strain exhibits neurotropism, causing neurological manifestations in a novel mouse model of EV71 infection. J Virol. 2012;86:2121–31.

  27. 27.

    Robin ED, Cross CE, Zelis R. Pulmonary edema. New Engl J Med. 1973;288:292–304.

  28. 28.

    Feng F, Jin Y, Duan L, et al. Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice. Environ Toxicol. 2015;31:2016–27.

  29. 29.

    Victorio CB, Xu Y, Ng Q, et al. A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema. Sci Rep. 2016;6:28876.

  30. 30.

    Sato T, Paquet-Fifield S, Harris NC, et al. VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury. J Pathol. 2016;239:152–61.

  31. 31.

    Rogers FB, Shackford SR, Trevisani GT, et al. Neurogenic pulmonary edema in fatal and nonfatal head injuries. J Trauma. 1995;39:860–6. discussion866-868

  32. 32.

    Xu F, Yao PP, Xia Y, et al. Enterovirus 71 infection causes severe pulmonary lesions in gerbils, meriones unguiculatus, which can be prevented by passive immunization with specific antisera. PLoS ONE. 2015;10:e0119173.

  33. 33.

    Menzies-Gow A, Ying S, Phipps S, et al. Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans. Clin Exp Allergy. 2004;34:1276–82.

  34. 34.

    Conroy DM, Williams TJ. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir Res. 2001;2:150–6.

  35. 35.

    Bacon AS, McGill JI, Anderson DF, et al. Adhesion molecules and relationship to leukocyte levels in allergic eye disease. Invest Ophthalmol Vis Sci. 1998;39:322–30.

  36. 36.

    Gudbjornsson B, Hallgren R, Nettelbladt O, et al. Phenotypic and functional activation of alveolar macrophages, T lymphocytes and NK cells in patients with systemic sclerosis and primary Sjogren’s syndrome. Ann Rheum Dis. 1994;53:574–9.

  37. 37.

    Reber LL, Hernandez JD, Galli SJ. The pathophysiology of anaphylaxis. J Allergy Clin Immunol. 2017;140:335–48.

  38. 38.

    Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822:21–33.

  39. 39.

    Venuprasad K, Kong YC, Farrar MA. Control of Th2-mediated inflammation by regulatory T cells. Am J Pathol. 2010;177:525–31.

  40. 40.

    Ebert S, Becker M, Lemmermann NA, et al. Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs. PLoS Pathog. 2014;10:e1004100.

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Acknowledgements

We thank Yinming Liang of Laboratory of Genetic Regulators in the Immune System, School of Laboratory Medicine, Xinxiang Medical University for helping us perform Flow Cytometry analysis. We thank Po-Hsun Huang of Department of Mechanical Engineering and Materials Science, Duke University for article’s edit. This work was funded by the National Natural Science Foundation of China (81172740); National Natural Science Foundation of China (81573205); Key scientific research projects in Colleges and Universities of Henan Province (15A330003); Outstanding doctoral thesis training fund of Zhengzhou University.

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Affiliations

  1. Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    • Yuefei Jin
    • , Chao Zhang
    • , Rongguang Zhang
    • , Shuaiyin Chen
    • , Dejian Dang
    • , Peng Zhang
    • , Yuanlin Xi
    •  & Guangcai Duan
  2. Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, Henan, People’s Republic of China

    • Hui Wang
    • , Xiangpeng Wang
    • , Rongguang Zhang
    • , Jingchao Ren
    •  & Weidong Wu
  3. Research Center for Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China

    • Hui Wang
    •  & Xiangpeng Wang
  4. School of Public Health, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China

    • Guangyuan Zhou
    • , Jingchao Ren
    •  & Weidong Wu
  5. Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China

    • Lu Chen
  6. Department of Immunology, Duke University Medical Center, Durham, NC, United States of America

    • Weiguo Zhang

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Guangcai Duan.

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