Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus

被引:276
作者
Zhou, Jie [1 ,2 ,3 ]
Li, Cun [2 ]
Zhao, Guangyu [4 ]
Chu, Hin [1 ,2 ,3 ]
Wang, Dong [2 ]
Yan, Helen Hoi-Ning [5 ]
Poon, Vincent Kwok-Man [2 ]
Wen, Lei [2 ]
Wong, Bosco Ho-Yin [2 ]
Zhao, Xiaoyu [2 ]
Chiu, Man Chun [2 ]
Yang, Dong [2 ]
Wang, Yixin [2 ]
Au-Yeung, Rex K. H. [5 ]
Chan, Ivy Hau-Yee [6 ]
Sun, Shihui [4 ]
Chan, Jasper Fuk-Woo [1 ,2 ,3 ,7 ,8 ]
To, Kelvin Kai-Wang [1 ,2 ,3 ,7 ,8 ]
Memish, Ziad A. [9 ,10 ,11 ]
Corman, Victor M. [12 ,13 ]
Drosten, Christian [12 ,13 ]
Hung, Ivan Fan-Ngai [14 ]
Zhou, Yusen [4 ]
Leung, Suet Yi [5 ]
Yuen, Kwok-Yung [1 ,2 ,3 ,7 ,8 ]
机构
[1] Univ Hong Kong, State Key Lab Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Queen Mary Hosp, Dept Microbiol, Pokfulam, Hong Kong, Peoples R China
[3] Univ Hong Kong, Res Ctr Infect & Immunol, Hong Kong, Hong Kong, Peoples R China
[4] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China
[5] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Pokfulam, Hong Kong, Peoples R China
[6] Queen Mary Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China
[7] Univ Hong Kong, Carol Yu Ctr Infect, Hong Kong, Hong Kong, Peoples R China
[8] Univ Hong Kong, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hong Kong, Hong Kong, Peoples R China
[9] Alfaisal Univ, Minist Hlth, Riyadh, Saudi Arabia
[10] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia
[11] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30322 USA
[12] Charite, Inst Virol, Berlin, Germany
[13] German Ctr Infect Res DZIF, Berlin, Germany
[14] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China
基金
中国国家自然科学基金;
关键词
SAUDI-ARABIA; MERS-COV; SOUTH-KOREA; TRANSMISSION; DISEASE; VIRUS; PATHOGENESIS; REPLICATION; OUTBREAK; ORGANOIDS;
D O I
10.1126/sciadv.aao4966
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Middle East respiratory syndrome coronavirus (MERS-CoV) has caused human respiratory infections with a high case fatality rate since 2012. However, the mode of virus transmission is not well understood. The findings of epidemiological and virological studies prompted us to hypothesize that the human gastrointestinal tract could serve as an alternative route to acquire MERS-CoV infection. We demonstrated that human primary intestinal epithelial cells, small intestine explants, and intestinal organoids were highly susceptible to MERS-CoV and can sustain robust viral replication. We also identified the evidence of enteric MERS-CoV infection in the stool specimen of a clinical patient. MERS-CoV was considerably resistant to fed-state gastrointestinal fluids but less tolerant to highly acidic fasted-state gastric fluid. In polarized Caco-2 cells cultured in Transwell inserts, apical MERS-CoV inoculation was more effective in establishing infection than basolateral inoculation. Notably, direct intragastric inoculation of MERS-CoV caused a lethal infection in human DPP4 transgenic mice. Histological examination revealed MERS-CoV enteric infection in all inoculated mice, as shown by the presence of virus-positive cells, progressive inflammation, and epithelial degeneration in small intestines, which were exaggerated in the mice pretreated with the proton pump inhibitor pantoprazole. With the progression of the enteric infection, inflammation, virus-positive cells, and live viruses emerged in the lung tissues, indicating the development of sequential respiratory infection. Taken together, these data suggest that the human intestinal tract may serve as an alternative infection route for MERS-CoV.
引用
收藏
页数:12
相关论文
共 46 条
[1]   Replication and Shedding of MERS-CoV in Upper Respiratory Tract of Inoculated Dromedary Camels [J].
Adney, Danielle R. ;
van Doremalen, Neeltje ;
Brown, Vienna R. ;
Bushmaker, Trenton ;
Scott, Dana ;
de Wit, Emmie ;
Bowen, Richard A. ;
Munster, Vincent J. .
EMERGING INFECTIOUS DISEASES, 2014, 20 (12) :1999-2005
[2]   Middle East respiratory syndrome coronavirus: epidemiology and disease control measures [J].
Al-Tawfiq, Jaffar A. ;
Memish, Ziad A. .
INFECTION AND DRUG RESISTANCE, 2014, 7 :281-287
[3]  
[Anonymous], 2013, PLOS CURR
[4]   Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study [J].
Assiri, Abdullah ;
Al-Tawfiq, Jaffar A. ;
Al-Rabeeah, Abdullah A. ;
Al-Rabiah, Fahad A. ;
Al-Hajjar, Sami ;
Al-Barrak, Ali ;
Flemban, Hesham ;
Al-Nassir, Wafa N. ;
Balkhy, Hanan H. ;
Al-Hakeem, Rafat F. ;
Makhdoom, Hatem Q. ;
Zumla, Alimuddin I. ;
Memish, Ziad A. .
LANCET INFECTIOUS DISEASES, 2013, 13 (09) :752-761
[5]   Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus [J].
Assiri, Abdullah ;
McGeer, Allison ;
Perl, Trish M. ;
Price, Connie S. ;
Al Rabeeah, Abdullah A. ;
Cummings, Derek A. T. ;
Alabdullatif, Zaki N. ;
Assad, Maher ;
Almulhim, Abdulmohsen ;
Makhdoom, Hatem ;
Madani, Hossam ;
Alhakeem, Rafat ;
Al-Tawfiq, Jaffar A. ;
Cotten, Matthew ;
Watson, Simon J. ;
Kellam, Paul ;
Zumla, Alimuddin I. ;
Memish, Ziad A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (05) :407-416
[6]   Environmental Contamination and Viral Shedding in MERS Patients During MERS-CoV Outbreak in South Korea [J].
Bin, Seo Yu ;
Heo, Jung Yeon ;
Song, Min-Suk ;
Lee, Jacob ;
Kim, Eun-Ha ;
Park, Su-Jin ;
Kwon, Hyeok-il ;
Kim, Se mi ;
Kim, Young-il ;
Si, Young-Jae ;
Lee, In-Won ;
Baek, Yun Hee ;
Choi, Won-Suk ;
Min, Jinsoo ;
Jeong, Hye Won ;
Choi, Young Ki .
CLINICAL INFECTIOUS DISEASES, 2016, 62 (06) :755-760
[7]   Unraveling the drivers of MERS-CoV transmission [J].
Cauchemez, Simon ;
Nouvellet, Pierre ;
Cori, Anne ;
Jombart, Thibaut ;
Garske, Tini ;
Clapham, Hannah ;
Moore, Sean ;
Mills, Harriet Linden ;
Salje, Henrik ;
Collins, Caitlin ;
Rodriquez-Barraquer, Isabel ;
Riley, Steven ;
Truelove, Shaun ;
Algarni, Homoud ;
Alhakeem, Rafat ;
AlHarbi, Khalid ;
Turkistani, Abdulhafiz ;
Aguas, Ricardo J. ;
Cummings, Derek A. T. ;
Van Kerkhove, Maria D. ;
Donnelly, Christl A. ;
Lessler, Justin ;
Fraser, Christophe ;
Al-Barrak, Ali ;
Ferguson, Neil M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (32) :9081-9086
[8]   Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease [J].
Chan, Jasper F. W. ;
Lau, Susanna K. P. ;
To, Kelvin K. W. ;
Cheng, Vincent C. C. ;
Woo, Patrick C. Y. ;
Yuen, Kwok-Yung .
CLINICAL MICROBIOLOGY REVIEWS, 2015, 28 (02) :465-522
[9]   Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures [J].
Chan, Renee W. Y. ;
Chan, Michael C. W. ;
Agnihothram, Sudhakar ;
Chan, Louisa L. Y. ;
Kuok, Denise I. T. ;
Fong, Joanne H. M. ;
Guan, Y. ;
Poon, Leo L. M. ;
Baric, Ralph S. ;
Nicholls, John M. ;
Peiris, J. S. Malik .
JOURNAL OF VIROLOGY, 2013, 87 (12) :6604-6614
[10]   Middle East Respiratory Syndrome Coronavirus Efficiently Infects Human Primary T Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways [J].
Chu, Hin ;
Zhou, Jie ;
Wong, Bosco Ho-Yin ;
Li, Cun ;
Chan, Jasper Fuk-Woo ;
Cheng, Zhong-Shan ;
Yang, Dong ;
Wang, Dong ;
Lee, Andrew Chak-Yiu ;
Li, Chuangen ;
Yeung, Man-Lung ;
Cai, Jian-Piao ;
Chan, Ivy Hau-Yee ;
Ho, Wai-Kuen ;
To, Kelvin Kai-Wang ;
Zheng, Bo-Jian ;
Yao, Yanfeng ;
Qin, Chuan ;
Yuen, Kwok-Yung .
JOURNAL OF INFECTIOUS DISEASES, 2016, 213 (06) :904-914