Abstract
Hand-foot-and-mouth disease is a self-limiting paediatric infectious disease commonly caused by Enterovirus A71 (Genus: Enterovirus, Family: Picornaviridae). Typical lesions in and around the hands, feet, oral cavity and other places may rarely be complicated by acute flaccid paralysis and acute encephalomyelitis. Although virus is readily cultured from skin vesicles and oral secretions, the cellular target/s of Enterovirus A71 in human skin and oral mucosa are unknown. In Enterovirus A71-infected human skin and oral mucosa organotypic cultures derived from the prepuce and lip biopsies, focal viral antigens and viral RNA were localized to cytoplasm of epidermal and mucosal squamous cells as early as 2 days post-infection. Viral antigens/RNA were associated with cytoplasmic vacuolation and cellular necrosis. Infected primary prepuce epidermal keratinocyte cultures showed cytopathic effects with concomitant detection of viral antigens from 2 days post-infection. Supernatant and/or tissue homogenates from prepuce skin organotypic cultures and primary prepuce keratinocyte cultures showed viral titres consistent with active viral replication. Our data strongly support Enterovirus A71 squamous epitheliotropism in the human epidermis and oral mucosa, and suggest that these organs are important primary and/or secondary viral replication sites that contribute significantly to oral and cutaneous viral shedding resulting in person-to-person transmission, and viraemia, which could lead to neuroinvasion.
Highlights
Person-to-person Enterovirus A71 (EV-A71) transmission is most commonly through fecal-oral and/or oral-oral routes because viruses can be detected in oral secretions and feces[2,9]
As viral replication sites contribute to viremia, squamous epitheliotropism may play an important role in neuroinvasion, which may be associated with higher viremia
Squamous cells derived from human prepuce and lip epidermis, and lip oral mucosa were found to be infected by EV-A71
Summary
Person-to-person EV-A71 transmission is most commonly through fecal-oral and/or oral-oral routes because viruses can be detected in oral secretions and feces[2,9]. Virus can be readily isolated from mouth ulcers and skin lesions[3,13,14,15,16,17], there have been very few pathological studies on infected human skin and oral cavity tissues, and no available evidence that squamous cells in these organs are susceptible to infection[10]. We hypothesize that squamous cells in the epidermis and oral cavity are susceptible to infection and represent important viral replication sites that contribute significantly to oral and cutaneous virus shedding and viremia. Our results strongly suggest that EV-A71 can readily infect human epidermal keratinocytes and oral mucosa squamous cells, confirming viral squamous epitheliotropism. Our results show that squamous epitheliotropism play a significant role in oral and cutaneous viral shedding leading to person-to-person viral transmission. As viral replication sites contribute to viremia, squamous epitheliotropism may play an important role in neuroinvasion, which may be associated with higher viremia
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