Histopathological features and distribution of EV71 antigens and SCARB2 in human fatal cases and a mouse model of enterovirus 71 infection.
Enterovirus 71 (EV71) is a neurotropic pathogen that causes hand, foot, and mouth disease. While infection is usually self-limiting, a minority of patients infected with EV71 develop severe neurological complications. In humans, EV71 has been reported to utilize the scavenger receptor class B, member 2 (SCARB2) as a receptor for infectious cellular entry. In this study, we define the pathological features of EV71-associated disease as well as the distribution of EV71 antigen and SCARB2 in human fatal cases and a mouse model. Histopathologically, human fatal cases showed severe central nervous system (CNS) changes, mainly in the brainstems, spinal cords, and thalamus. These patient further exhibited pulmonary edema and necrotic enteritis. Immunohistochemical analysis of human fatal cases demonstrated that EV71 antigen and SCARB2 were observed mainly in neurons, microglia cells and inflammatory cells in the CNS, and epithelial cells in the intestines. However, skeletal muscle tissue was negative for EV71 antigen. In a mouse model of EV71 infection, we observed massive necrotic myositis, different degrees of viral diseases in CNS, and extensive interstitial pneumonia. In mice, EV71 exhibits strong myotropism compared to the neurotropism seen in humans. EV71 antigen was detected in the spinal cord and brainstem of mice. However, there was no clear correlation between mouse SCARB2 and EV71 antigen distribution in the mouse model, consistent with previous results that SCARB2 functions as a receptor for EV71 in humans but not mice. The EV71-induced lesions seen in the mouse model resembled the pathological changes seen in human samples. These results increase our understanding of EV71 pathogenesis and will inform further work developing a mouse model for EV71 infection.
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: pinyucau@gmail.com.
Pin
P
Yu
Department of Pathology, Peking University Health Science Center, Beijing 100191, China. Electronic address: wjshgao@bjmu.edu.cn.
Zifen
Z
Gao
Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China. Electronic address: zong-yy@qq.com.
Yuanyuan
Y
Zong
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: bllmsl@aliyun.com.
Linlin
L
Bao
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: xull@cnilas.org.
Lili
L
Xu
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: dengwei717@163.com.
Wei
W
Deng
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: icyli1019@hotmail.com.
Fengdi
F
Li
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: qqmei-qiqi@163.com.
Qi
Q
Lv
Department of Respiratory & Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China. Electronic address: zcgao@bjmu.edu.cn.
Zhancheng
Z
Gao
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: yanfxu@gmail.com.
Yanfeng
Y
Xu
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: yaoyanfeng1981@aliyun.com.
Yanfeng
Y
Yao
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China. Electronic address: qinchuan@pumc.edu.cn.
Chuan
C
Qin
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis*; D018955:CD36 Antigens / Q000032:analysis; D002675:Child, Preschool; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000502:physiology*; D005260:Female; D016679:Genome, Viral; D006232:Hand, Foot and Mouth Disease / Q000473:pathology* / Q000821:virology*; D006801:Humans; D007223:Infant; D051907:Lysosomal Membrane Proteins / Q000032:analysis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000235:genetics; D051116:Receptors, Scavenger / Q000032:analysis*; D011991:Receptors, Virus / Q000032:analysis*; D017422:Sequence Analysis, DNA; D056189:Viral Tropism
D000956:Antigens, Viral; D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; D012367:RNA, Viral; D051116:Receptors, Scavenger; D011991:Receptors, Virus; C074299:SCARB2 protein, human; C489452:Scarb2 protein, mouse
Enterovirus 71; Hand; Human cases; Mouse model; Pathology; and mouth disease; foot