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Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner

Nature Microbiology volume 3, pages 611–621 (2018)Cite this article

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Abstract

Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic use on host cells is understudied. Here we identify an antiviral effect of commonly used aminoglycoside antibiotics. We show that topical mucosal application of aminoglycosides prophylactically increased host resistance to a broad range of viral infections including herpes simplex viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral replication in primary human cells. This antiviral activity was independent of the microbiota, because aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a marked upregulation of transcripts for interferon-stimulated genes (ISGs) following aminoglycoside application. ISG induction was mediated by Toll-like receptor 3, and required Toll/interleukin-1-receptor-domain-containing adapter-inducing interferon-β signalling adaptor, and Interferon regulatory factors 3 and 7, transcription factors that promote ISG expression. XCR1+ dendritic cells, which uniquely express Toll-like receptor 3, were recruited to the vaginal mucosa upon aminoglycoside treatment and were required for ISG induction. These results highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral resistance in vivo.

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Fig. 1: Vaginal application of neomycin confers prophylactic and post-exposure antiviral protection against HSV-2 in a microbiota-independent manner.
Fig. 2: Vaginal application of most aminoglycosides induces interferon-stimulated genes, which is linked to antiviral protection.
Fig. 3: Aminoglycosides confer broad protection against both RNA and DNA viruses.
Fig. 4: Aminoglycosides mediate antiviral immunity via the TLR3–TRIF–IRF3/7 signalling pathway.
Fig. 5: Recruited DCs are required for ISG induction by neomycin.
Fig. 6: Recruited XCR1+ DCs are required for ISG induction.

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Acknowledgements

The authors thank Y. Kong for his help with analysing the microarray data, and H. Dong for animal support. The authors also thank P. Biswal for help with visualizing the microarray data. This study was supported by funding from the National Institutes of Health (AI054359, R56AI125504, R01EB000487 and 1R21AI131284 to A.I.). A.I. and A.L.G. are Investigator and Faculty Scholar of Howard Hughes Medical Institute. S.G. and M.V.K. are recipients of the James Hudson Brown–Alexander Brown Coxe Postdoctoral Fellowships at Yale University.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, New Haven, CT, USA

    Smita Gopinath, Andrew L. Goodman & Akiko Iwasaki

  2. Department of Immunobiology, Yale University, New Haven, CT, USA

    Smita Gopinath, Myoungjoo V. Kim, Tasfia Rakib, Patrick W. Wong & Akiko Iwasaki

  3. New England Discovery Partners, Branford, CT, USA

    Michael van Zandt

  4. Department of Microbial Pathogenesis and Microbial Sciences Institute, Yale University, New Haven, CT, USA

    Natasha A. Barry & Andrew L. Goodman

  5. Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

    Tsuneyasu Kaisho

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Contributions

S.G. and A.I. planned the project, designed the experiments, interpreted the data and wrote the paper. S.G., M.V.K., T.R. and P.W.W. designed and carried out the experiments. N.A.B. and A.L.G. provided reagents and help with germ-free experiments. T.K., M.v.Z. and A.L.G. provided reagents and feedback.

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Correspondence to Akiko Iwasaki.

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Supplementary Table 1

Genes upregulated in vaginal tissue upon neomycin treatment. Significant genes are in red.

Supplementary Table 2

Extended table of P values.

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Gopinath, S., Kim, M.V., Rakib, T. et al. Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner. Nat Microbiol 3, 611–621 (2018). https://doi.org/10.1038/s41564-018-0138-2

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