title: Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis.
abstract: Enterovirus 71 (EV71; family Picornaviridae, species human Enterovirus A) usually causes hand, foot, and mouth disease, which may rarely be complicated by fatal encephalomyelitis. We investigated extra-central nervous system (extra-CNS) tissues capable of supporting EV71 infection and replication, and have correlated tissue infection with expression of putative viral entry receptors, scavenger receptor B2 (SCARB2), and P-selectin glycoprotein ligand-1 (PSGL-1). Formalin-fixed, paraffin-embedded CNS and extra-CNS tissues from seven autopsy cases were examined by IHC and in situ hybridization to evaluate viral antigens and RNA. Viral receptors were identified with IHC. In all seven cases, the CNS showed stereotypical distribution of inflammation and neuronal localization of viral antigens and RNA, confirming the clinical diagnosis of EV71 encephalomyelitis. In six cases in which tonsillar tissues were available, viral antigens and/or RNA were localized to squamous epithelium lining the tonsillar crypts. Tissues from the gastrointestinal tract, pancreas, mesenteric nodes, spleen, and skin were all negative for viral antigens/RNA. Our novel findings strongly suggest that tonsillar crypt squamous epithelium supports active viral replication and represents an important source of viral shedding that facilitates person-to-person transmission by both the fecal-oral or oral-oral routes. It may also be a portal for viral entry. A correlation between viral infection and SCARB2 expression appears to be more significant than for PSGL-1 expression.
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Yaoxin
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kien Chai
authors.initials: KC
authors.lastname: Ong
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Zifen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Xishun
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Anderson
authors.affiliation: Department of Pathology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McNutt
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address: wongkt@ummc.edu.my.
authors.forename: Kum Thong
authors.initials: KT
authors.lastname: Wong
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing, China. Electronic address: lumin@hsc.pku.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D002490:Central Nervous System / Q000821:virology; D002648:Child; D004679:Encephalomyelitis / Q000821:virology*; D029821:Enterovirus A, Human / Q000502:physiology*; D004848:Epithelium / Q000821:virology; D006801:Humans; D007249:Inflammation; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009055:Mouth; D014066:Palatine Tonsil / Q000821:virology*; D012367:RNA, Viral / Q000235:genetics; D051116:Receptors, Scavenger / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D014779:Virus Replication; D055815:Young Adult
chemical_list: D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D012367:RNA, Viral; D051116:Receptors, Scavenger; D011991:Receptors, Virus; C074299:SCARB2 protein, human