Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections

• Published in: Cell reports (Cambridge) Vol. 22; no. 13; pp. 3440 - 3453.e6
• Main Authors: Thackray, Larissa B., Handley, Scott A., Gorman, Matthew J., Poddar, Subhajit, Bagadia, Prachi, Briseño, Carlos G., Theisen, Derek J., Tan, Qing, Hykes, Barry L., Lin, Hueylie, Lucas, Tiffany M., Desai, Chandni, Gordon, Jeffrey I., Murphy, Kenneth M., Virgin, Herbert W., Diamond, Michael S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2018; Elsevier
• Subjects: Administration, Oral; Aedes; Ampicillin - adverse effects; Ampicillin - pharmacology; Animals; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Cecum - drug effects; Cecum - microbiology; Chlorocebus aethiops; Dengue virus; Female; flavivirus; Flavivirus - isolation & purification; gut microbiota; immunity; Male; Mice; Mice, Inbred C57BL; Microbiota - drug effects; oral antibiotics; pathogenesis determinants; risk factors; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Vero Cells; West Nile virus; Zika virus; Zika Virus Infection - drug therapy; Zika Virus Infection - immunology; Zika Virus Infection - microbiology; Zika Virus Infection - pathology; risk factors; pathogenesis determinants; West Nile virus; oral antibiotics; Zika virus; immunity; Dengue virus; gut microbiota; flavivirus
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.001

Although the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8+ T cells associated with increased infection and immunopathology. Abx treatments that resulted in enhanced WNV susceptibility generated changes in the overall structure of the gut bacterial community and in the abundance of specific bacterial taxa. As little as 3 days of treatment with ampicillin was sufficient to alter host immunity and WNV outcome. Our results identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections. [Display omitted] •Oral antibiotics increase susceptibility of mice to severe flavivirus disease•Oral antibiotics impair development of optimal antiviral T cell responses•Oral antibiotics alter bacterial abundance and community structure•Just 3 days of oral ampicillin is sufficient to alter flavivirus outcome Thackray et al. observed increased susceptibility to West Nile, Zika, and Dengue virus infections following oral antibiotic treatment in mice. Antibiotics altered the bacterial abundance and community structure and the development of optimal T cell immunity. These data suggest that antibiotics may have deleterious consequences for subsequent flavivirus infections.