Zika virus shedding in the stool and infection through the anorectal mucosa in mice

Abstract

Zika virus (ZIKV) has elicited global concern due to its unique biological features, unusual transmission routes, and unexpected clinical outcomes. Although ZIKV transmission through anal intercourse has been reported in humans, it remains unclear if ZIKV is detectable in the stool, if it can infect the host through the anal canal mucosa, and what the pathogenesis of such a route of infection might be in the mouse model. Herein, we demonstrate that ZIKV RNA can be recovered from stools in multiple mouse models, as well as from the stool of a ZIKV patient. Remarkably, intra-anal (i.a.) inoculation with ZIKV leads to efficient infection in both Ifnar1^−/− and immunocompetent mice, characterized by extensive viral replication in the blood and multiple organs, including the brain, small intestine, testes, and rectum, as well as robust humoral and innate immune responses. Moreover, i.a. inoculation of ZIKV in pregnant mice resulted in transplacental infection and delayed fetal development. Overall, our results identify the anorectal mucosa as a potential site of ZIKV infection in mice, reveal the associated pathogenesis of i.a. infection, and highlight the complexity of ZIKV transmission through anal intercourse.

These authors contributed equally: Chunfeng Li, Yong-Qiang Deng and Shulong Zu

These authors contributed equally: Chunfeng Li, Yong-Qiang Deng and Shulong Zu

Acknowledgements

We thank Dr. Pengcheng Pu (Institute of Biophysics, Chinese Academy of Science) and all members of our team for helpful discussions. C-.F.Q. was supported by the NSFC Excellent Young Scientist award (81522025), the Innovative Research Group (81621005), and the Newton Advanced Fellowship from the UK Academy of Medical Sciences (81661130162). This work was supported by the CAMS Initiative Innovative Medicine (No. 2016-I2M-1-005), the National Natural Science Foundation of China (U170220023, 81772176, 31670883, 91542201, 81590765, and 31500145), Major Project for "Significant New Drugs Innovation and Development" (2015ZX09102023), NIH R01 AI140718, AI069120, AI056154 and AI078389 502 grants, MOST (China, 2016YFD0500304), and the Guangzhou Science and Technology Program for Public Wellbeing (No. 201704020229). C.L. was supported by the PUMC Youth Fund (No. 3332016125).

Author Contributions

C-.F.Q. and G.C. jointly directed the research. C.L., Y-.Q.D. and S.Z. performed the experiments. C.L. designed experiments and wrote the first draft of the manuscript. N.Q., J.S., M.T., X.J., N-.N.Z., H-.L.D., Y-.P.X., L-.Z.Z., F-.C.Z., X-.F.L. and A.W. helped perform the experiments and contributed to data analysis. All authors contributed to the writing to the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0170-6).

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