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Recent advances in enterovirus A71 pathogenesis: a focus on fatal human enterovirus A71 infection

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Abstract

Enterovirus A71 (EV-A71) is one of the major pathogens responsible for hand, foot, and mouth disease (HFMD). Many HFMD outbreaks have been reported throughout the world in the past decades. Compared with other viruses, EV-A71 infection is more frequently associated with severe neurological complications and even death in children. EV-A71 can also infect adults and cause severe complications and death, although such cases are very uncommon. Although fatal cases of EV-A71 infection have been reported, the underlying mechanisms of EV-A71 infection, especially the mode of viral spread into the central nervous system (CNS) and mechanisms of pulmonary edema, which is considered to be the direct cause of death, have not yet been fully clarified, and more studies are needed. Here, we first summarize the pathological findings in various systems of patients with fatal EV-A71 infections, focussing in detail on gross changes, histopathological examination, tissue distribution of viral antigens and nucleic acids, systemic inflammatory cell infiltration, and tissue distribution of viral receptors and their co-localization with viral antigens. We then present our conclusions about viral dissemination, neuropathogenesis, and the mechanism of pulmonary edema in EV-A71 infection, based on pathological findings.

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Abbreviations

EV-A71:

Enterovirus A71

HFMD:

Hand, foot, and mouth disease

CNS:

Central nervous system

IHC:

Immunohistochemistry

ISH:

in situ hybridization

MRI:

Magnetic resonance imaging

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Acknowledgments

This research was supported by the Natural Science Foundation of Zhejiang province (grant number LQ20H090002), the Natural Science Foundation of Ningbo (grant numbers 2019A610376, 2021J120, and 2021J130), the Ningbo Public Welfare Project (202002N3168), and the K.C. Wong Magna Fund in Ningbo University.

Funding

Natural Science Foundation of Zhejiang province (grant no. LQ20H090002); Natural Science Foundation of Ningbo (grant nos. 2019A610376, 2021J120, 2021J130); Ningbo Public Welfare Project (grant no. 202002N3168).

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  1. Jingjun Xing and Ke Wang have contributed equally as first author.

Authors and Affiliations

  1. Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Science, School of Medicine, Ningbo University, No. 818 Fenghua Road, Jiangbei District, Ningbo, 315211, Zhejiang Province, P. R. China

    Jingjun Xing, Geng Wang, Na Li & Yanru Zhang

  2. The Affiliated Hospital of Medical School, Ningbo University, No. 247 Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang Province, P. R. China

    Ke Wang

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JX and KW wrote the paper. YZ conceived the idea and supervised the progress of the project. GW and NL helped prepare the figures and perform the analysis with constructive discussions.

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Xing, J., Wang, K., Wang, G. et al. Recent advances in enterovirus A71 pathogenesis: a focus on fatal human enterovirus A71 infection. Arch Virol 167, 2483–2501 (2022). https://doi.org/10.1007/s00705-022-05606-4

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