Enhanced Infection of Liver Sinusoidal Endothelial Cells in a Mouse Model of Antibody-induced Severe Dengue Disease

Zellweger, R. M., Prestwood, T. R., and Shresta, S.

Cell Host & Microbe, 7, 128-139, 2010

Speaker：Siao-Fen Yeh (葉曉芬)                                 Time：15:10~16:00, Oct. 20, 2010

Commentator：Dr. Chih-Li Lilian Hsu (胥直利老師)          Place：Room 601

Abstract：

Dengue virus (DV) is a member of the flaviviruses. Dengue infection causes diseases ranging from dengue fever to lethal dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). DHF/DSS is characterized by rapid onset of capillary leakage accompanied by thrombocytopenia, altered hemostasis, and damage to the liver indicated by increase in aspartate amino-transferase and alanine-transferase (1). Many studies suggest that DHF/DSS occurs in patients who have acquired DV-reactive antibody prior infection. This subneutralizing levels of DV-specific antibodies exacerbate disease by increasing infection of cells with FcγRs is described as a phenomenon called “antibody-dependent enhancement (ADE)” (2) .  Although ADE phenomenon causes severe DV diseases, however, there is no suitable animal model to study the mechanism of ADE and ADE-related pathogenesis. In this study, the authors used the interferon deficient mice and infected the mice with DV2 together with special anti-DV antibody. Their data showed low platelet counts; increased vascular permeability in the liver; and gastrointestinal hemorrhage, which parallel with the progression of DHF/DSS. They also revealed that the viral load was increased in the liver, small intestine, spleen, and serum in mice receiving DV2 infection together with anti-DV antibody treatment. Liver is an organ which showed higher viral load at 48 hr post infection. Furthermore, the authors used flow cytometry to detect the cells showing DV prM⁺ designated “liver sinusoidal endothelial cells (LSECs) .” LSECs produced the highest virus particles in the mice under ADE conditions. The authors also reveal that the clinical syndromes of LSECs in DV2-infected mice under ADE conditions were similar with DHF/DSS. Collectively, the authors developed an ADE mouse model which is a IFN deficient mouse system to study mechanisms of ADE, DV pathogenesis, and immune responses to DV.

References：

1.          Halstead, S. B. (2007) Dengue. Lancet 370, 1644-1652

2.          Halstead, S. B. (2003) Neutralization and antibody-dependent enhancement of dengue viruses. Adv. Virus Rev. 60, 421-467.