Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections
Larissa B. Thackray,
Scott A. Handley,
Matthew J. Gorman,
Subhajit Poddar,
Prachi Bagadia,
Carlos G. Briseño,
Derek J. Theisen,
Qing Tan,
Barry L. Hykes, Jr.,
Hueylie Lin,
Tiffany M. Lucas,
Chandni Desai,
Jeffrey I. Gordon,
Kenneth M. Murphy,
Herbert W. Virgin,
Michael S. Diamond
Affiliations
Larissa B. Thackray
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Scott A. Handley
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Matthew J. Gorman
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Subhajit Poddar
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Prachi Bagadia
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Carlos G. Briseño
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Derek J. Theisen
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Qing Tan
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Barry L. Hykes, Jr.
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Hueylie Lin
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Tiffany M. Lucas
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Chandni Desai
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Jeffrey I. Gordon
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, Saint Louis, MO 63110, USA
Kenneth M. Murphy
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University School of Medicine, Saint Louis, MO 63110, USA
Herbert W. Virgin
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Michael S. Diamond
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA; Corresponding author
Summary: 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. : 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. Keywords: West Nile virus, Dengue virus, Zika virus, flavivirus, oral antibiotics, gut microbiota, risk factors, pathogenesis determinants, immunity
