PT  - JOURNAL ARTICLE
AU  - Zhou, Jie
AU  - Li, Cun
AU  - Zhao, Guangyu
AU  - Chu, Hin
AU  - Wang, Dong
AU  - Yan, Helen Hoi-Ning
AU  - Poon, Vincent Kwok-Man
AU  - Wen, Lei
AU  - Wong, Bosco Ho-Yin
AU  - Zhao, Xiaoyu
AU  - Chiu, Man Chun
AU  - Yang, Dong
AU  - Wang, Yixin
AU  - Au-Yeung, Rex K. H.
AU  - Chan, Ivy Hau-Yee
AU  - Sun, Shihui
AU  - Chan, Jasper Fuk-Woo
AU  - To, Kelvin Kai-Wang
AU  - Memish, Ziad A.
AU  - Corman, Victor M.
AU  - Drosten, Christian
AU  - Hung, Ivan Fan-Ngai
AU  - Zhou, Yusen
AU  - Leung, Suet Yi
AU  - Yuen, Kwok-Yung
TI  - Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus
AID  - 10.1126/sciadv.aao4966
DP  - 2017 Nov 01
TA  - Science Advances
PG  - eaao4966
VI  - 3
IP  - 11
4099  - http://advances.sciencemag.org/content/3/11/eaao4966.short
4100  - http://advances.sciencemag.org/content/3/11/eaao4966.full
SO  - Sci Adv2017 Nov 01; 3
AB  - 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.