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

• Authors: Jie Zhou, University of Hong Kong; Cun Li, University of Hong Kong; Guangyu Zhao, Beijing Institute of Microbiology and Epidemiology; Hin Chu, University of Hong Kong; Dong Wang, University of Hong Kong; Helen Hoi-Ning Yan, University of Hong Kong; Vincent Kwok-Man Poon, University of Hong Kong; Lei Wen, University of Hong Kong; Bosco Ho-Yin Wong, University of Hong Kong; Xiaoyu Zhao, University of Hong Kong; Man Chun Chiu, University of Hong Kong; Dong Yang, University of Hong Kong; Yixin Wang, University of Hong Kong; Rex K. H. Au-Yeung, University of Hong Kong; Ivy Hau-Yee Chan, Queen Mary Hospital; Shihui Sun, Beijing Institute of Microbiology and Epidemiology; Jasper Fuk-Woo Chan, University of Hong Kong; Kelvin Kai-Wang To, University of Hong Kong; Ziad Ahmed Memish, Emory University; Victor M. Corman, Charité–Universitätsmedizin Berlin; Christian Drosten, Charité–Universitätsmedizin Berlin; Ivan Fan-Ngai Hung, University of Hong Kong; Yusen Zhou, Beijing Institute of Microbiology and Epidemiology; Suet Yi Leung, University of Hong Kong; Kwok-Yung Yuen, University of Hong Kong
• Journal Title: Science Advances
• Volume: Volume 3, Number 11
• Publisher: American Association for the Advancement of Science | 2017-11-01, Pages eaao4966-eaao4966
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1126/sciadv.aao4966
• Subjects: Biology, Virology; Health Sciences, Immunology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; SAUDI-ARABIA; MERS-COV; SOUTH-KOREA; TRANSMISSION; DISEASE; VIRUS; PATHOGENESIS; REPLICATION; OUTBREAK; ORGANOIDS

Abstract

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.