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.