Abstract

A recent epidemic of Zika virus in the Americas, affecting well over a million people, caused substantial mortality and morbidity, including Guillain–Barre syndrome, microcephaly and other fetal developmental defects1,2. Preventive and therapeutic measures that specifically target the virus are not readily available. The transmission of Zika virus is predominantly mosquito-borne, and Aedes aegypti mosquitoes serve as a key vector for Zika virus3. Here, to identify salivary factors that modulate mosquito-borne Zika virus infection, we focused on antigenic proteins in mice that were repeatedly bitten by mosquitoes and developed antibodies against salivary proteins. Using a yeast surface display screen, we identified five antigenic A. aegypti salivary proteins in mice. Antiserum against one of these five proteins—A. aegypti bacteria-responsive protein 1 (AgBR1)—suppressed early inflammatory responses in the skin of mice bitten by Zika-virus-infected mosquitoes. AgBR1 antiserum also partially protected mice from lethal mosquito-borne—but not needle-injected—Zika virus infection. These data suggest that AgBR1 is a target for the prevention of mosquito-transmitted Zika virus infection.

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Data availability

The data that support the findings of this study are available from the corresponding authors on request. The RNA-seq data have been deposited in the Gene Expression Omnibus under the accession number GSE125194.

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Acknowledgements

We thank S. Shresta at the La Jolla Institute for Allergy and Immunology for originally providing us with the AG129 mouse strain. We also thank S. Ren, Y.-M. Chuang, S. Householder, S. Stanley, H. Sproch and B. V. Wyk for supporting experiments and analysing data. The imaging mass cytometry was conducted at the Yale CyTOF facility and the RNA-seq service was conducted at the Yale Stem Cell Center Genomics Core facility, which was supported by the Connecticut Regenerative Medicine Research Fund and the Li Ka Shing Foundation. This work was supported by NIH grant nos AI089992 and AI127865, and the Japan Society for the Promotion of Science Overseas Research Fellowships. E.F. and A.I. are investigators with the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Section of Infectious Diseases, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA

    • Ryuta Uraki
    • , Andrew K. Hastings
    • , Alejandro Marin-Lopez
    •  & Erol Fikrig
  2. Department of Neurology, School of Medicine, Yale University, New Haven, CT, USA

    • Tomokazu Sumida
    •  & David A. Hafler
  3. Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA

    • Tomokazu Sumida
    • , Takehiro Takahashi
    • , Akiko Iwasaki
    •  & David A. Hafler
  4. Department of Microbial Pathogenesis, School of Medicine, Yale University, New Haven, CT, USA

    • Jonathan R. Grover
  5. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    • Akiko Iwasaki
    •  & Erol Fikrig
  6. Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA

    • Ruth R. Montgomery

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Contributions

R.U. and E.F. designed the experiments. R.U. performed the majority of the experiments and analysed the data. A.K.H., A.M.-L. and J.R.G. assisted in the experiments with mosquitoes. R.U. and T.S. performed the analysis of the RNA-seq. T.T. performed the histopathological analyses. A.I., D.A.H. and R.R.M. contributed experimental suggestions and strengthened the writing of the manuscript. R.U. and E.F wrote the manuscript. All authors reviewed, critiqued and provided comments on the text.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Erol Fikrig.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–12, Supplementary Tables 1–3 and Supplementary Table 6.

  2. Reporting Summary

  3. Supplementary Table 4

    List of upregulated genes at the bite site of mice treated with control (naïve) serum.

  4. Supplementary Table 5

    List of GSEA-enriched pathway at bite sites in mice treated with control serum using hallmark gene sets (http://software.broadinstitute.org/gsea/msigdb/genesets.jsp?collection=H).

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DOI

https://doi.org/10.1038/s41564-019-0385-x