Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) causes sporadic zoonotic disease and healthcare-associated outbreaks in human. MERS is often complicated by acute respiratory distress syndrome (ARDS) and multi-organ failure1,2. The high incidence of renal failure in MERS is a unique clinical feature not often found in other human coronavirus infections3,4. Whether MERS-CoV infects the kidney and how it triggers renal failure are not understood5,6. Here, we demonstrated renal infection and apoptotic induction by MERS-CoV in human ex vivo organ culture and a nonhuman primate model. High-throughput analysis revealed that the cellular genes most significantly perturbed by MERS-CoV have previously been implicated in renal diseases. Furthermore, MERS-CoV induced apoptosis through upregulation of Smad7 and fibroblast growth factor 2 (FGF2) expression in both kidney and lung cells. Conversely, knockdown of Smad7 effectively inhibited MERS-CoV replication and protected cells from virus-induced cytopathic effects. We further demonstrated that hyperexpression of Smad7 or FGF2 induced a strong apoptotic response in kidney cells. Common marmosets infected by MERS-CoV developed ARDS and disseminated infection in kidneys and other organs. Smad7 and FGF2 expression were elevated in the lungs and kidneys of the infected animals. Our results provide insights into the pathogenesis of MERS-CoV and host targets for treatment.
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Acknowledgements
This work was supported in part by donations from the Shaw Foundation, R. Yu and C. Yu, the Providence Foundation (in memory of the late Lui Hac Minh), Cheer Master Investments, and Respiratory Viral Research Foundation Limited; and funding from Seed Funding for the Theme-based Research Scheme and Strategic Research Theme Fund from the University of Hong Kong, the Hong Kong Health and Medical Research Fund (13121102, 14130822, 14131392 and HKM-15-M01), the Hong Kong Research Grants Council (N_HKU728/14, HKU1/CRF/11G and 17124415) and the National Science and Technology Major Projects of Infectious Disease (2012ZX10004501-004). The authors thank A. Ng, C. Lau, L.-K. Tang and members of the Centre for Genomic Sciences, The University of Hong Kong, for their technical support.
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M.-L.Y. and K.-Y.Y. conceived and designed the study. M.-L.Y. and L.J. performed most experiments with the help of K.-H.C., J.L.L.T., H.C. and J.Z. M.-L.Y. and A.K.L.T. performed bioinformatics analysis. Y.Y., J.F.W.C., V.K.M.P., W.D., B.-J.Z. and C.Q. constructed the animal model, provided samples and analysed the data. K.-F.C., Q.Z., T.-M.C. and S.Y. performed histopathological analysis. J.F.W.C., K.K.W.T. and M.-K.Y. provided samples and assisted with the establishment of ex vivo organ culture. S.K.P.L. and P.C.Y.W. provided advice, assisted with sequencing and analysed the data. M.-L.Y., C.Q. and K.-Y.Y. wrote the manuscript. Y.Y., J.F.W.C., H.C., J.L.L.T., J.Y.N.L., D.-Y.J. and P.W.M. provided advice and contributed to data analysis and manuscript preparation. C.Q. and K.-Y.Y. secured funding and conducted trouble-shooting. All authors read and approved the final manuscript.
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Yeung, ML., Yao, Y., Jia, L. et al. MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2. Nat Microbiol 1, 16004 (2016). https://doi.org/10.1038/nmicrobiol.2016.4
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DOI: https://doi.org/10.1038/nmicrobiol.2016.4
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