title: Subcutaneous infection with non-mouse adapted Dengue virus D2Y98P strain induces systemic vascular leakage in AG129 mice.
abstract: BACKGROUND
  Dengue (DEN) is a mosquito-borne viral disease which has become an increasing economic and health burden for the tropical and subtropical world. Plasma leakage is the most life threatening condition of DEN and may lead to hypovolaemic shock if not properly managed.
  
  
  METHODS
  We recently reported a unique dengue virus strain (D2Y98P) which upon intraperitoneal (IP) administration to immunocompromised mice led to systemic viral dissemination, intestine damage, liver dysfunction, and increased vascular permeability, hallmarks of severe DEN in patients (Tan et al, PLoS Negl Trop Dis 2010;4:e672).
  
  
  RESULTS
  Here we report the clinical manifestations and features observed in mice subcutaneously (SC) infected with D2Y98P, which is a route of administration closer to natural infection. Similar to the IP route, increased vascular permeability, intestine damage, liver dysfunction, transient lymphopenia (but no thrombocytopenia) were observed in the SC infected mice. Furthermore, the SC route of infection was found more potent than the IP route whereby higher viral titers and earlier time-of-death rates were measured. In addition, various staining approaches revealed structurally intact blood vessels in the moribund animals despite pronounced systemic vascular leakage, as reported in dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) patients. Interestingly, measurement of soluble mediators involved in vascular permeability indicated that vascular leakage may occur at an early stage of the disease, as proposed in DEN patients.
  
  
  CONCLUSIONS
  We believe that this novel mouse model of DEN-associated vascular leakage will contribute to a better understanding of DEN pathogenesis and represents a relevant platform for testing novel therapeutic treatments and interventions.
authors.affiliation: Department of Microbiology, Immunology Programme, National University of Singapore.
authors.forename: Grace Kx
authors.initials: GK
authors.lastname: Tan
authors.forename: Jowin Kw
authors.initials: JK
authors.lastname: Ng
authors.forename: Angeline Hy
authors.initials: AH
authors.lastname: Lim
authors.forename: Kim Pin
authors.initials: KP
authors.lastname: Yeo
authors.forename: Veronique
authors.initials: V
authors.lastname: Angeli
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D003715:Dengue / Q000503:physiopathology*; D003716:Dengue Virus / Q000472:pathogenicity*; D004195:Disease Models, Animal; D016867:Immunocompromised Host; D051379:Mice; D019595:Severe Dengue / Q000503:physiopathology*