Current status of hand-foot-and-mouth disease

Abstract

Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.

Keywords: Epidemiological characteristic; Hand-foot-and-mouth disease; Innate immune response; Sequelae; Treatment.

Fig. 1

Complications and sequelae of HFMD

Fig. 2

The life cycle of Enterovirus. Enterovirus (EVs) enter the host cells by binding to receptors or by exosome-mediated endocytosis and release positive-strand RNA. The RNA undergoes transcription and translation after being covalently linked to the viral protein VPg (3B). The translated polyprotein is hydrolyzed by various proteases into 10 separate major proteins, including VP0, VP1, VP3, 2A-C, 3A-D, where VP0 is subsequently hydrolyzed to VP2 and VP4. VP1-4 are assigned to participate in the assembly of viral protein coats, while 2A-C, 3A-D are directed to participate in the replication of viral genetic material. Finally, the viral RNA and coat are assembled and processed into mature viruses, which are then co-packaged with host organelle decomposers in vesicles and secreted out of the cell, or directly released by exocytosis

Fig. 3

Distribution of patients with HFMD in the world. A EV-A71; B CVA16; C CVA6; D CVA10. Areas marked in orange indicate that EV-A71/CVA16/CVA6/CVA10 epidemic have been reported

Fig. 4

Phylogenetic analyses of the Enterovirus. Phylogenetic analyses of the EV-A71 (A), CVA16 (B), CVA6 (C) and CVA10 (D) circulating globally based on full length sequence of the VP1 gene worldwide available from GenBank were conducted in MEGA 7 using the neighbor-joining method. The bootstrap test was performed with 1000 replications. The evolutionary distances were written on the branch. We selected the representative VP1 sequences (EV-A71, n = 84; CVA16, n = 47; CVA6, n = 39; and CVA10, n = 56) from GenBank according to the country of origin, year of isolation and other information. All the strains are labelled using the following format: ‘accession number’/ ‘country of origin’/ ‘year of isolation’. All selected representative strains are marked with distinct colors according to different genotypes/sub-genotypes. The prototypes strains marked with yellow circles and red circles indicate the outgroups. The genotyping reference strains of different genotypes/sub-genotypes of CVA6 and CVA10 are marked as black triangles

Fig. 5

Innate immune evasion by Enterovirus. ssRNA, dsRNA and various proteins of EVs during replication and translation can activate and escape innate immunity through different pathways. (1) Viral RNA is recognized by TLR3, TLR7, TLR8 and TLR9, and then activates TRAF, TRIF, MyD88 and their downstream linker molecules, causing phosphorylation of IRF3, IRF7 and NF-κB to translocate to the nucleus, and finally promote the secretion of interferons (IFNs). (2) 2A protease(pro) and 3Cpro are mainly recognized by RIG-I and MDA5, and bind to MAVS in mitochondria to activate TRAF3 and TRAF6. However, prior to signaling to IRF1, IRF3, and IRF7, host ncRNAs regulated by the virus target and inhibit the activation of TRAF, ultimately reducing IFNs production. (3) Binding of IFNs to the receptor IFNAR activates downstream JAK1 and Tyk2, which promotes the phosphorylation and translocation of STAT1 and STAT2 to the nucleus, initiating transcription of IFN-stimulated response elements (ISREs). However, this pathway is directly or indirectly inhibited by 3Cpro, 2Apro, and 2Bpro, resulting in decreased secretion of IFNs. (4) Assembly of the NLRP3 inflammasome requires the sensor NLRP3, the adaptor protein ASC, and pro-caspase-1. However, host-invading viruses can activate and inhibit the formation of the NLRP3 inflammatory complex. Solid line with arrows at the end indicates activation; dashed line with a small line at the end indicates inhibition; scissor indicates cutting