Hand-Foot-and-Mouth Disease-Associated Enterovirus and the Development of Multivalent HFMD Vaccines

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Abstract

Hand-foot-and-mouth disease (HFMD) is an infectious disease of children caused by more than 20 types of enteroviruses, with most cases recovering spontaneously within approximately one week. Severe HFMD in individual children develops rapidly, leading to death, and is associated with other complications such as viral myocarditis and type I diabetes mellitus. The approval and marketing of three inactivated EV-A71 vaccines in China in 2016 have provided a powerful tool to curb the HFMD epidemic but are limited in cross-protecting against other HFMD-associated enteroviruses. This review focuses on the epidemiological analysis of HFMD-associated enteroviruses since the inactivated EV-A71 vaccine has been marketed, collates the progress in the development of multivalent enteroviruses vaccines in different technical routes reported in recent studies, and discusses issues that need to be investigated for safe and effective HFMD multivalent vaccines.

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Anthony J. Sadler, Bryan Williams (2008)

Key Points Interferons (IFNs) are key components of the innate immune response and the first line of defence against virus infection. Among the hundreds of IFN-induced genes, only a few have been ascribed direct antiviral activity in vivo: ISG15 (IFN-stimulated protein of 15 kDa), the Mx (myxovirus resistance) proteins, 2′,5′-oligoadenylate synthetase (OAS)-regulated ribonuclease L (RNaseL) and protein kinase R (PKR). These proteins separately block viral transcription, degrade viral RNA, inhibit translation or modify the proteasome to control all steps of viral replication. ISG15 is part of a ubiquitin-like pathway that modulates the function of numerous protein targets. The Mx proteins seem to survey exocytic events and mediate vesicle trafficking to trap viral components. The OAS-regulated RNaseL pathway degrades single-stranded RNA in virus-infected cells. PKR inhibits translation and participates in signal transduction. Additional functions of each of these proteins are still being uncovered, suggesting they have broader roles in the host immune response.

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The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

Yiwen Zhang, Yingshi Chen, Yuzhuang Li … (2021)

We report that SARS-CoV-2 utilizes its ORF8 protein as a unique mechanism to alter the expression of surface MHC-Ι expression to evade immune surveillance. Our study is significant for providing an understanding of the pathogenesis of SARS-CoV-2 and will provide additional perspective to the intensive ongoing investigation into the mechanism and function of T cell antiviral immunity in COVID-19. COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2–infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.

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The life cycle of non-polio enteroviruses and how to target it

Frank J. M. van Kuppeveld, Jeroen Strating, Hendrik Jan Thibaut … (2018)

The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host-receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines.