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

There is a critical need to better understand the host effects of commonly used antibiotics. 52 53 Here, we found that topical delivery of an aminoglycoside antibiotic to the mucosa induced 54 significant alteration of host gene expression, inducing increased expression of antiviral 55 interferon-stimulated genes (ISGs). Aminoglycoside-mediated ISG induction resulted in 56 significant protection against genital HSV-2 infection and significantly reduced Zika virus 57 replication. Aminoglycoside-mediated antiviral protection was independent of the host 58 microbiota, as intravaginal aminoglycoside treatment protected germ-free mice form HSV-59 2 infection. This protection mechanism operates in the vaginal mucosa and nasal mucosa, 60 as intranasal aminoglycoside treatment increased ISG expression in the lung and 61 aminoglycoside pre-treated hosts had increased survival after highly virulent influenza A 62 virus infection. ISG expression was dependent on TLR3 and downstream signaling 63 pathway, and robust recruitment of TLR3-expressing XCR1+ dendritic cells to the vaginal 64 mucosa. Our results reveal an unexpected induction of antiviral state by commonly used 65 aminoglycoside antibiotics. 66 author/funder. All rights reserved. No reuse allowed without permission.