title: Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons.
abstract: BACKGROUND
  Disseminated or fatal Zika virus (ZIKV) infections were reported in immunosuppressed patients. Existing interferon-signaling/receptor-deficient mouse models may not be suitable for evaluating treatment effects of recombinant interferons.
  
  
  METHODS
  We developed a novel mouse model for ZIKV infection by immunosuppressing BALB/c mice with dexamethasone.
  
  
  RESULTS
  Dexamethasone-immunosuppressed male mice (6-8weeks) developed disseminated infection as evidenced by the detection of ZIKV-NS1 protein expression and high viral loads in multiple organs. They had ≥10% weight loss and high clinical scores soon after dexamethasone withdrawal (10dpi), which warranted euthanasia at 12dpi. Viral loads in blood and most tissues at 5dpi were significantly higher than those at 12dpi (P<0.05). Histological examination revealed prominent inflammatory infiltrates in multiple organs, and CD45+ and CD8+ inflammatory cells were seen in the testis. These findings suggested that clinical deterioration occurred during viral clearance by host immune response. Type I interferon treatments improved clinical outcome of mice (100% vs 0% survival).
  
  
  CONCLUSIONS
  Besides virus dissemination, inflammation of various tissues, especially orchitis, may be potential complications of ZIKV infection with significant implications on disease transmission and male fertility. Interferon treatment should be considered in patients at high risks for ZIKV-associated complications when the potential benefits outweigh the side effects of treatment.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address: jfwchan@hku.hk.
authors.forename: Jasper Fuk-Woo
authors.initials: JF
authors.lastname: Chan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Anna Jinxia
authors.initials: AJ
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Chris Chung-Sing
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Cyril Chik-Yan
authors.initials: CC
authors.lastname: Yip
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Winger Wing-Nga
authors.initials: WW
authors.lastname: Mak
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Houshun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Vincent Kwok-Man
authors.initials: VK
authors.lastname: Poon
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kah-Meng
authors.initials: KM
authors.lastname: Tee
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jian-Piao
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jessica Oi-Ling
authors.initials: JO
authors.lastname: Tsang
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kenn Ka-Heng
authors.initials: KK
authors.lastname: Chik
authors.affiliation: Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan 571101, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Yin
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Rex Kwok-Him
authors.initials: RK
authors.lastname: Au-Yeung
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address: kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D016867:Immunocompromised Host; D007370:Interferon Type I / Q000494:pharmacology*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009920:Orchitis / Q000188:drug therapy / Q000821:virology*; D019562:Viral Load; D000071244:Zika Virus / Q000187:drug effects* / Q000276:immunology*; D000071243:Zika Virus Infection / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000821:virology*
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D003907:Dexamethasone
keywords: Animal; Flavivirus; Interferon; Model; Mouse; Orchitis; Steroid; Testis; Treatment; Zika