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. IMPORTANCEMosquito-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.T he genus Flavivirus of the family Flaviviridae contains emerging and reemerging enveloped RNA viruses that cause serious diseases in humans and animals, including dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV). A group ...

An updated review of avian-origin Tembusu virus: a newly emerging avian Flavivirus

“…DEF, GEF and DF-1) and mosquito cell lines (i.e. C6/36 and Aedes albopictus) [26][27][28]. In addition, an artificial infection study found that BALB/c mice and Kunming mice are susceptible to duck TMUV after intracerebral inoculation, but not subcutaneous (s.c.) orintranasal (i.n.)…”

“…The field strain of TMUV (TMUV-SDMS) was found to grow well in the mosquito C6/36 cell line, monkey Vero cells and duck embryo fibroblast (DEF) cells. According to phylogenetic analysis of the E and NS5 genes, TMUV-SDMS is closely related to duckorigin TMUV, which causes severe egg-drop disease [27]. Further in vivo experimental data have shown that TMUV RNA replicates well in Cx.…”

Transcriptome Analysis Reveals the Neuro-Immune Interactions in Duck Tembusu Virus-Infected Brain

“…Another study demonstrated The same scenario, with all infected ducks (1, 3, and 7 week of age) displaying viral encephalitis [18]. Furthermore, The duck Tembusu virus exhibits neurovirulence and age-dependent neuroinvasiveness in BALB/c mice [5,19]. However, The interaction between DTMUV neurovirulence and neuro-immune responses remains unknown.In order to reveal The interaction between DTMUV neurovirulence and neuro-immune responses, we used DTMUV to infect 10-day-old specific pathogen free (SPF) ducks in The current study and harvested The duck brains at 12, 24, and 48 h post infection (hpi).…”

“…Another study demonstrated The same scenario, with all infected ducks (1, 3, and 7 week of age) displaying viral encephalitis [18]. Furthermore, The duck Tembusu virus exhibits neurovirulence and age-dependent neuroinvasiveness in BALB/c mice [5,19]. However, The interaction between DTMUV neurovirulence and neuro-immune responses remains unknown.…”

“…It causes tremendous economic losses in The poultry industry in China and Southeast Asia [4]. In addition, It is capable of infecting and causing cytopathic effects in various mammalian cell lines [5]. Moreover, in one study, DTMUV-specific antibodies and viral RNA were detected in duck farm workers [6].…”