**2. Virology of enterovirus**

Enteroviruses are single-stranded, positive-sense RNA viruses belonging to the *Picornaviri‐ dae* family. They are associated with various human and animal diseases, and are tradition‐ ally classified into 4 groups, namely, Coxsackie A viruses, Coxsackie B viruses, echoviruses and polioviruses, depending on the clinical presentation. Recently, however, enteroviruses have been named numerically e.g. EV70 and EV71 in recognition of the similarities among the 4 groups noted on genomic studies [2].

RNA viruses are known for their high spontaneous mutation rate, which is attributed to the absence of proof reading in viral RNA polymerases. This invariably leads to the emergence of new enteroviruses and consequently, new clinical presentations. Enterovirus 71 was first described in California USA in 1969 [3] and will arguably be the next most important entero‐ virus after the eradication of poliovirus.

© 2013 Chia and Chu; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The enterovirus is a small, non-enveloped spherical particle around 30nm in diameter. The viral genomic RNA is encapsidated within the capsid shell comprising the VP1-4 capsid pro‐ teins. The capsid proteins are arranged into a symmetrical icosahedral lattice. These capsid proteins recognize receptors on host cells and demonstrate antigenicity. The viral genome is translated into a polyprotein around 250kDa which then undergoes cleavage via the viral proteases. The viral non-structural proteins 2A-C and 3A-D are essential for the replication of the virus within infected cells [4].

While coinfections with other enteroviruses did not appear to increase the risk of neurologi‐ cal complications, an association was found between patients who were coinfected with dengue viruses and neurological symptoms [5]. Similarly, in the retrospective study of 423 patients, those with CNS involvement were more likely to have EV71 (21%) instead of cox‐ sackie A virus infection (16%). In addition, rate of disease progression and severity was re‐

The reservoir of human pathogenic enterovirus is humans and transmission of enteroviruses occurs through the fecal-oral route via droplets or in utero [28]. Infection starts in the gastro‐ intestinal system with proliferation in the pharynx or intestinal lymph nodes before dissemi‐

*In vitro* studies of EV71 show that the virus binds to DLD-1 intestinal cells which express sialic acid (SA) linked glycan on the cell surface [29]. Decreasing O-linked glycans or gly‐ colipids on the cell surface decreased EV71 infection of DLD-1 intestinal cells but this was not reproducible on decreasing N-linked glycans. SA linked glycans isolated from human milk also inhibited EV71 infection of DLD-1 intestinal cells [29], suggesting poten‐

The first step for a virus to infect the CNS is to cross the blood brain barrier (BBB). The BBB serves as a physical barrier, consisting of endothelial cells joined to each other by tight junc‐ tions and surrounded by foot processes of astrocytes, preventing access to the CNS. The me‐ ninges, choroid plexus and ependymal cells lining the ventricles also prevent access. Within the CNS are also dendritic cells and macrophages that detect pathogens and contribute to the host defense response. In utero, the BBB has not fully matured and viruses crossing into

Several RNA viruses causing neurological symptoms e.g. poliovirus, enter the CNS through axonal transport from the peripheral nervous system (PNS), circumventing the blood brain

quently migrate through ependymal cell layer of the BBB into the CNS [30]. Other enterovi‐ ruses such as EV71 cross the BBB by binding to receptors e.g. P-selectin glycoprotein ligand-1, infecting cells (leucocytes and lymphocytes) that normally cross the BBB [31], hitchhiking their way into the CNS. Enterovirus 71 and coxsackie-viruses have also been shown to bind to scavenger receptor class B member 2 (SCARB2) found on fibroblasts and GPI-anchored protein decay-accelerating factor found on epithelial cells in the CNS, gaining entry into the CNS [28, 32]. SCARB2 participates in membrane transportation and the re-or‐ ganization of endosomal and lysosomal compartments [33]. The coxsackievirus and adeno‐ virus receptor (CAR) also facilitates viral entry in a caveolin-dependent or independent manner [32, 34] while human poliovirus receptor, an adhesion molecule, is used by human poliovirus in a caveolin independent manner but dynamin-dependent manner to gain entry [32, 35]. The receptors and varying method of entry in different cell types may explain for

myeloid cells which subse‐

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ported to be greater in EV71 infection [19].

the placental circulation can also result in CNS infection.

barrier. Coxsackie-virus B3 on the other hand targets nestin+

**4. Pathogenesis**

tial therapeutic use.

nating to the rest of the body.

Phylogenetic studies of enterovirus 71 have identified 3 genotypes and numerous subtypes. The 3 genotypes are A, B and C, whereas the subtypes are classified numerically. Increased neurovirulence have been attributed to certain subtypes, such as genotype C1 [5]. Still, the exact pathogenesis for the variation in disease presentation is unknown.
