In-cell infection: a novel pathway for Epstein-Barr virus infection mediated by cell-in-cell structures.
Epstein-Barr virus (EBV) can infect both susceptible B lymphocytes and non-susceptible epithelial cells (ECs). Viral tropism analyses have revealed two intriguing means of EBV infection, either by a receptor-mediated infection of B cells or by a cell-to-cell contact-mediated infection of non-susceptible ECs. Herein, we report a novel "in-cell infection" mechanism for EBV infection of non-susceptible ECs through the formation of cell-in-cell structures. Epithelial CNE-2 cells were invaded by EBV-infected Akata B cells to form cell-in-cell structures in vitro. Such unique cellular structures could be readily observed in the specimens of nasopharyngeal carcinoma. Importantly, the formation of cell-in-cell structures led to the autonomous activation of EBV within Akata cells and subsequent viral transmission to CNE-2 cells, as evidenced by the expression of viral genes and the presence of virion particles in CNE-2 cells. Significantly, EBV generated from in-cell infected ECs displayed altered tropism with higher infection efficacy to both B cells and ECs. In addition to CNE-2 tumor cells, cell-in-cell structure formation could also mediate EBV infection of NPEC1-Bmi1 cells, an immortalized nasopharyngeal epithelial cell line. Furthermore, efficient infection by this mechanism involved the activation of the PI3K/AKT signaling pathway. Thus, our study identified "in-cell infection" as a novel mechanism for EBV infection. Given the diversity of virus-infected cells and the prevalence of cell-in-cell structures during chronic infection, we speculate that "in-cell infection" is likely a general mechanism for EBV and other viruses to infect non-susceptible ECs.
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Chao
C
Ni
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Yuhui
Y
Chen
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Musheng
M
Zeng
Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Rongjuan
R
Pei
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Yong
Y
Du
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Linquan
L
Tang
School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Mengyi
M
Wang
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Yazhuo
Y
Hu
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Hanyu
H
Zhu
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Meifang
M
He
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Xiawei
X
Wei
The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
Shan
S
Wang
Laboratory of Cell Engineering, Institute of Biotechnology, Beijing 100071, China.
Xiangkai
X
Ning
Laboratory of Cell Engineering, Institute of Biotechnology, Beijing 100071, China.
Manna
M
Wang
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Jufang
J
Wang
Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China.
Li
L
Ma
Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Xinwen
X
Chen
Laboratory of Cell Engineering, Institute of Biotechnology, Beijing 100071, China.
Qiang
Q
Sun
Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Hong
H
Tang
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Ying
Y
Wang
Institute of Life Sciences, Chinese PLA General Hospital and School of Bioscience and Bioengineering, South China University of Technology, Key Laboratory of Normal aging and Geriatric & the State Key Laboratory of Kidney, Beijing 100853 & the Provincial Key Laboratory of Biotechnology, Guangdong 510006, China.
Xiaoning
X
Wang
D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002277:Carcinoma; D002450:Cell Communication; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology*; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000821:virology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D019869:Phosphatidylinositol 3-Kinases