title: The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling.
abstract: Flaviviruses pose a significant threat to both animals and humans. Recently, a novel flavivirus, duck Tembusu virus (DTMUV), was identified to be the causative agent of a serious duck viral disease in Asia. Its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. Here, we demonstrate that DTMUV is not pathogenic for nonhuman primates and is highly sensitive to mammal type I interferon (IFN) signaling. In vitro assays demonstrated that DTMUV infected and replicated efficiently in various mammalian cell lines. Further tests in mice demonstrated high neurovirulence and the age-dependent neuroinvasiveness of the virus. In particular, the inoculation of DTMUV into rhesus monkeys did not result in either viremia or apparent clinical symptoms, although DTMUV-specific humoral immune responses were detected. Furthermore, we revealed that although avian IFN failed to inhibit DTMUV in avian cells, DTMUV was more sensitive to the antiviral effects of type I interferon than other known human-pathogenic flaviviruses. Knockout of the type I IFN receptor in mice caused apparent viremia, viscerotropic disease, and mortality, indicating a vital role of IFN signaling in protection against DTMUV infection. Collectively, we provide direct experimental evidence that this novel avian-origin DTMUV possesses a limited capability to establish infection in immunocompetent primates due to its decreased antagonistic activity in the mammal IFN system. Furthermore, our findings highlight the potential risk of DTMUV infection in immunocompromised individuals and warrant studies on the cross-species transmission and pathogenesis of this novel flavivirus.
  
  
  
  Mosquito-borne flaviviruses comprise a large group of pathogenic and nonpathogenic members. The pathogenic flaviviruses include dengue, West Nile, and Japanese encephalitis viruses, and the nonpathogenic flaviviruses normally persist in a natural cycle and rarely cause disease in humans. A novel flavivirus, DTMUV (also known as duck egg drop syndrome flavivirus [DEDSV]) was identified in 2012 in ducks and then rapidly spread to several Asian countries. This new flavivirus was then shown to infect multiple avian species, resulting in neurological symptoms with unknown routes of transmission. There is public concern regarding its potential transmission from birds to humans and other nonavian hosts. Our present study shows that the mammalian IFN system can efficiently eliminate DTMUV infection and that the emergence of severe DTMUV-associated disease in mammals, especially humans, is unlikely. Currently, DTMUV infection mostly affects avian species.
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Hong-Jiang
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|Graduate School, Anhui Medical University, Hefei, China.
authors.forename: Long
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Yan-Peng
authors.initials: YP
authors.lastname: Xu
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Deng
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Xing-Yao
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: E-De
authors.initials: ED
authors.lastname: Qin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.|National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China qincf@bmi.ac.cn.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.|Graduate School, Anhui Medical University, Hefei, China.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Qin
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004372:Ducks / Q000821:virology*; D005260:Female; D005416:Flavivirus / Q000472:pathogenicity*; D018177:Flavivirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011201:Poultry Diseases / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017471:Receptors, Interferon / Q000502:physiology*; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D017471:Receptors, Interferon