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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Seminars in Immunopathology Open Access 29 April 2022
Annals of Clinical Microbiology and Antimicrobials Open Access 21 May 2021
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Badal, S., Her, Y. F. & Maher, L. J. Nonantibiotic effects of fluoroquinolones in mammalian cells. J. Biol. Chem. 290, 22287–22297 (2015).
Kalghatgi, S. et al. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in mammalian cells. Sci. Transl. Med. 5, 192ra85 (2013).
Moullan, N. et al. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep. 10, 1681–1691 (2015).
Yang, J. H. et al. Antibiotic-induced changes to the host metabolic environment inhibit drug efficacy and alter immune function. Cell Host Microbe 22, 757–765.
Linehan, M. M. et al. In vivo role of nectin-1 in entry of herpes simplex virus type 1 (HSV-1) and HSV-2 through the vaginal mucosa. J. Virol. 78, 2530–2536 (2004).
Shin, H. & Iwasaki, A. Generating protective immunity against genital herpes. Trends Immunol. 34, 487–494 (2013).
Corey, L. & Schiffer, J. T. Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat. Med. 19, 280–290 (2013).
Khoury-Hanold, W. et al. Viral spread to enteric neurons links genital HSV-1 infection to toxic megacolon and lethality. Cell Host Microbe 19, 788–799 (2016).
McDermott, M. R. et al. Immunity in the female genital tract after intravaginal vaccination of mice with an attenuated strain of herpes simplex virus type 2. J. Virol. 51, 747–753 (1984).
Busscher, G. F., Rutjes, F. P. J. T. & van Delft, F. L. 2-Deoxystreptamine: central scaffold of aminoglycoside antibiotics. Chem. Rev. 105, 775–792 (2005).
Wilson, D. N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat. Rev. Microbiol. 12, 35–48 (2014).
Morgun, A. et al. Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks. Gut 64, 1732–1743 (2015).
Meier, E. et al. A family of interferon-induced Mx-related mRNAs encodes cytoplasmic and nuclear proteins in rat cells. J. Virol. 62, 2386–2393 (1988).
Staeheli, P., Grob, R., Meier, E., Sutcliffe, J. G. & Haller, O. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol. Cell. Biol. 8, 4518–4523 (1988).
Haller, O., Staeheli, P., Schwemmle, M. & Kochs, G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 23, 154–163 (2015).
Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).
Grimm, D. et al. Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. Proc. Natl Acad. Sci. USA 104, 6806–6811 (2007).
Yockey, L. J. et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell 166, 1247–1256 (2016).
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).
Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).
Schneider, W. M., Chevillotte, M. D. & Rice, C. M. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32, 513–545 (2014).
Schmid, S., Mordstein, M., Kochs, G., Garcia-Sastre, A. & tenOever, B. R. Transcription factor redundancy ensures induction of the antiviral state. J. Biol. Chem. 285, 42013–42022 (2010).
Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014).
Shortman, K. & Heath, W. R. The CD8+ dendritic cell subset. Immunol. Rev. 234, 18–31 (2010).
Schulz, O. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005).
Heng, T. S. P. et al. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
Miller, J. C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).
Crozat, K. et al. Cutting edge: expression of XCR1 defines mouse lymphoid-tissue resident and migratory dendritic cells of the CD8+ type. J. Immunol. 187, 4411–4415 (2011).
Yamazaki, C. et al. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J. Immunol. 190, 6071–6082 (2013).
Begg, E. J. & Barclay, M. L. Aminoglycosides—50 years on. Br. J. Clin. Pharmacol. 39, 597–603 (1995).
Rizzi, M. D. & Hirose, K. Aminoglycoside ototoxicity. Curr. Opin. Otolaryngol. Head Neck Surg. 15, 352–357 (2007).
Matsui, J. I., Gale, J. E. & Warchol, M. E. Critical signaling events during the aminoglycoside-induced death of sensory hair cells in vitro. J. Neurobiol. 61, 250–266 (2004).
Cheng, A. G., Cunningham, L. L. & Rubel, E. W. Mechanisms of hair cell death and protection. Curr. Opin. Otolaryngol. Head. Neck Surg. 13, 343–348 (2005).
Wargo, K. A. & Edwards, J. D. Aminoglycoside-induced nephrotoxicity. J. Pharm. Pract. 27, 573–577 (2014).
Laurent, G., Kishore, B. K. & Tulkens, P. M. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem. Pharmacol. 40, 2383–2392 (1990).
Ryu, D. H. & Rando, R. R. Aminoglycoside binding to human and bacterial A-site rRNA decoding region constructs. Bioorg. Med. Chem. 9, 2601–2608 (2001).
Recht, M. I., Fourmy, D., Blanchard, S. C., Dahlquist, K. D. & Puglisi, J. D. RNA sequence determinants for aminoglycoside binding to an A-site rRNA model oligonucleotide. J. Mol. Biol. 262, 421–436 (1996).
Walter, F., Vicens, Q. & Westhof, E. Aminoglycoside–RNA interactions. Curr. Opin. Chem. Biol. 3, 694–704 (1999).
Rausch, K. et al. Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus. Cell Rep. 18, 804–815 (2017).
Retallack, H. et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl Acad. Sci. USA 113, 14408–14413 (2016).
Porter, J. D. et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium. J. Antimicrob. Chemother. 71, 2767–2781 (2016).
Sistigu, A. et al. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).
Hashino, E. & Shero, M. Endocytosis of aminoglycoside antibiotics in sensory hair cells. Brain Res. 704, 135–140 (1995).
Myrdal, S. E. & Steyger, P. S. TRPV1 regulators mediate gentamicin penetration of cultured kidney cells. Hear. Res. 204, 170–182 (2005).
Assas, B. M., Wakid, M. H., Zakai, H. A., Miyan, J. A. & Pennock, J. L. Transient receptor potential vanilloid 1 expression and function in splenic dendritic cells: a potential role in immune homeostasis. Immunology 147, 292–304 (2016).
Moestrup, S. K. et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J. Clin. Invest. 96, 1404–1413 (1995).
Christensen, E. I. & Birn, H. Megalin and cubilin: multifunctional endocytic receptors. Nat. Rev. Mol. Cell Biol. 3, 258–268 (2002).
Iyoda, T. et al. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J. Exp. Med. 195, 1289–1302 (2002).
Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat. Immunol. 10, 488–495 (2009).
Hong, S. et al. Evidence that antibiotics bind to human mitochondrial ribosomal RNA has implications for aminoglycoside toxicity. J. Biol. Chem. 290, 19273–19286 (2015).
Sun, Q. et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24, 633–642 (2006).
Horisberger, M. A., Staeheli, P. & Haller, O. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc. Natl Acad. Sci. USA 80, 1910–1914 (1983).
Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).
Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).
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.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
This article is cited by
Seminars in Immunopathology (2022)
Annals of Clinical Microbiology and Antimicrobials (2021)
Target-based drug discovery, ADMET profiling and bioactivity studies of antibiotics as potential inhibitors of SARS-CoV-2 main protease (Mpro)
Sulfamethoxazole drug stress upregulates antioxidant immunomodulatory metabolites in Escherichia coli
Nature Microbiology (2020)
Nature Microbiology (2020)