Microbiota-independent antiviral protection conferred by aminoglycoside antibiotics

Smita Gopinath; Myoungjoo V. Kim; Tasfia Rakib; Patrick W. Wong; Michael van Zandt; Natasha A. Barry; Tsuneyasu Kaisho; Andrew L. Goodman; Akiko Iwasaki

Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic 27 use on host cells is understudied. We have identified a novel antiviral effect of commonly 28 used aminoglycoside antibiotics. We show that mucosal application of aminoglycosides 29 increased host resistance to a broad range of viral infections including herpes simplex 30 viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral 31 replication in primary human cells. This antiviral activity was independent of the microbiota 32 as aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a 33 marked upregulation of transcripts for interferon-stimulated genes (ISGs) following 34 aminoglycoside application. ISG induction was mediated by TLR3, and required TIR-35 domain-containing adapter-inducing interferon-β (TRIF), signaling adaptor, and interferon 36 regulatory factors 3 (IRF3) and IRF7, transcription factors that promote ISG expression. 37 XCR1+ dendritic cells, which uniquely express TLR3, were recruited to the vaginal mucosa 38 upon aminoglycoside treatment and were required for ISG induction. These results 39 highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral 40 resistance in vivo. 41