Tonsillar Crypt Epithelium Is an Important Extra-Central Nervous System Site for Viral Replication in EV71 Encephalomyelitis

He, Yusen; Ong, Kien Chai; Gao, Zifen; Zhao, Xi-shun; Anderson, Virginia; McNutt, Michael A.; Wong, Kum Thong; Lu, Min

doi:10.1016/j.ajpath.2013.11.009

Cited by 53 publications

(57 citation statements)

References 35 publications

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“…First, based on the reported data suggesting the tonsillar crypt as a portal for viral entry (He et al, 2014), the observation from confocal microscopy confirmed the green fluorescence signal from EGFP-EV71 in tonsillar tissue (Figure 3A). Furthermore, this fluorescence signal co-localized with the red fluorescence signal emanating from antibodies against CD11b and CD141 (Figures 3B,C).…”

Section: Resultssupporting

confidence: 64%

“…The study reported by He and colleagues suggested that the tonsillar crypt epithelium was an important extra CNS site for viral replication in EV71 encephalomyelitis, and their study showed the damage caused by the epithelial tissue-associated inflammatory reaction and the high viral load in the tonsils (He et al, 2014). Our results showed a similar increasing viral load and inflammatory cell infiltration in the tonsillar tissue, except for the damage we observed in the epithelium, and also identified the existence of the virus in the CD141 + cells of the tonsils by confocal microscopy, the same as in the other lymph nodes around the respiratory tract.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study by He et al using viable tissues from autopsy cases suggested that the tonsillar crypt epithelium was an important extra-central nervous system site for viral replication in EV71 encephalomyelitis (He et al, 2014). This suggests that lymphokinesis might provide a pathway for viral infection.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques

Zhao

Zhang

et al. 2017

Front. Cell. Infect. Microbiol.

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Enterovirus 71 (EV71) is one of the main pathogens responsible for hand, foot, and mouth disease (HFMD). Infection with EV71 can lead to severe clinical disease via extensive infections of either the respiratory or alimentary tracts in children. Based on the previous pathological study of EV71 infections in neonatal rhesus macaques, our work using this animal model and an EV71 chimera that expresses enhanced green fluorescent protein (EGFP-EV71) primarily explored where EV71 localizes and proliferates, and the subsequent initiation of the pathological process. The chimeric EGFP-EV71 we constructed was similar to the wild-type EV71 (WT-EV71) virus in its biological characteristics. Similar clinical manifestations and histo-pathologic features were equally displayed in neonatal rhesus macaques infected with either WT-EV71 or EGFP-EV71 via the respiratory route. Fluorescent signal tracing in tissues from the animals infected with EGFP-EV71 showed that EV71 proliferated primarily in the respiratory tract epithelium and the associated lymphoid tissues. Immunofluorescence and flow cytometry analyses revealed that EV71 was able to enter a pre-conventional dendritic cell (DC) population at the infection sites. The viremia identified in the macaques infected by WT-EV71 or EGFP-EV71 was present even in the artificial presence of a specific antibody against the virus. Our results suggest that EV71 primarily proliferates in the respiratory tract epithelium followed by subsequent entry into a pre-cDC population of DCs. These cells are then hijacked by the virus and they can potentially transmit the virus from local sites to other organs through the blood circulation during the infection process. Our results suggest that the EV71 infection process in this DC population does not interfere with the induction of an independent immune response against the EV71 infection in the neonatal macaques.

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques

Zhao

Zhang

et al. 2017

Front. Cell. Infect. Microbiol.

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“…SCARB2, but not PSGL-1, expression was observed in EV71 antigen-positive neurons and in epithelial cells in the crypts of palatine tonsils from patients that died of acute neurological disease. 60 Thus, it is suggested that SCARB2 plays an essential role in establishing EV71 infection and in the development of neurological disease in humans. This hypothesis is supported by the transgenic expression of human SCARB2 in mice.…”

Section: In Vivo Importance Of Scarb2mentioning

confidence: 99%

“…64 However, PSGL-1 expression has not been reported in the neurons of the central nervous system and the epithelial cells in the crypt of palatine tonsil. 60 No reports suggest that PB and non-PB strains have different pathological outcomes. Furthermore, the transgenic expression of PSGL-1 is not sufficient to cause disease.…”

Section: Psgl-1mentioning

confidence: 99%

Receptors for enterovirus 71

Yamayoshi

Fujii

Koike

2014

Emerging Microbes & Infections

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Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

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miR‐127‐5p negatively regulates enterovirus 71 replication by directly targeting SCARB2

Feng

Chen

et al. 2017

FEBS Open Bio

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Enterovirus 71 ( EV 71) is the major causative agent of hand‐foot‐and‐mouth disease in young children and can cause severe cerebral and pulmonary complications and even fatality. This study aimed at elucidating whether and how EV 71 infection is regulated by a cellular micro RNA , miR‐127‐5p. We found that miR‐127‐5p can downregulate the expression of SCARB 2, a main receptor of EV 71, by targeting two potential sites in its 3′ UTR region and inhibit EV 71 infection. Meanwhile, miR‐127‐5p expression was upregulated during EV 71 infection. Notably, transfecting cells with miR‐127‐5p mimics led to a significant decrease in viral replication, while inhibition of endogenous miR‐127‐5p facilitated viral replication. Furthermore, our evidence showed that miR‐127‐5p did not affect postentry viral replication. Taken together, these results indicated that miR‐127‐5p inhibited EV 71 replication by targeting the SCARB 2 mRNA .

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Tonsillar Crypt Epithelium Is an Important Extra-Central Nervous System Site for Viral Replication in EV71 Encephalomyelitis

Cited by 53 publications

References 35 publications

Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques

Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques

Receptors for enterovirus 71

miR‐127‐5p negatively regulates enterovirus 71 replication by directly targeting SCARB2

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