Role of mast cells in mouse models of dengue virus infection

• Main Authors: Ya-TingChu, 朱雅婷
• Other Authors: Yee-Shin Lin
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/65432590300076014500

碩士 === 國立成功大學 === 微生物及免疫學研究所 === 101 === Dengue virus (DENV) is a member of the family Flaviviridae and consists of four serotypes DENV-1, -2, -3 and -4. DENV infection causes dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). It has been speculated that mast cells may play a role in DENV disease. For example, DHF patients exhibit increased level of urinary histamine which is a major granule-associated mediator from mast cells. However, the precise involvement of mast cells in DENV infection is unclear. Previous studies reported that DENV-infected human mast cells induce production of cytokines (TNF-α, IL-6, IL-1β) and chemokines (MIP-1α, MIP-1β, RANTES). These findings suggest that mast cells may play a role in vascular perturbation as well as leukocyte recruitment. Another study showed that DENV-infected mast cells recruit NK and NKT cells to the infection site to clear virus. In this study, we used mouse models to clarify the roles of mast cells in DENV infection. We have established a DENV-induced hemorrhage model in STAT1-/- mice which are susceptible to DENV. Our data showed that DENV but not UV-inactivated DENV enhanced mast cell degranulation in STAT1-/- mice. However, the degranulated mast cells were not infected by DENV. In addition, our previous study showed that anti-ΔC NS1 and anti-DJ NS1 antibodies (Abs) provided protection in DENV-infected STAT1-/- mice. In this study, we also found that treatment with anti-ΔC NS1 and anti-DJ NS1 Abs resulted in a reduction of mast cell degranulation and RANTES and MCP-1 production as well as macrophage infiltration. We hypothesize that DENV-infected endothelial cells or macrophages produce chemokines and further induce mast cell activation. Interactions between macrophages and mast cells may result in more cytokine production and cause endothelial cell damage or activation. We further investigated the roles of mast cells in mast cell-deficient KitW-sh/W-sh mice. The results showed a more prolonged bleeding time in DENV-infected KitW-sh/W-sh mice than in wild-type (WT) mice. More NS3 antigen was detected at the local infection site in DENV-infected KitW-sh/W-sh mice than in DENV-infected WT mice. The basal levels of MCP-1, IP-10, and RANTES at the local infection site were higher in KitW-sh/W-sh mice than in WT mice. After DENV infection, the expression of MCP-1, IP-10, and RANTES at the local infection site were significantly increased in KitW-sh/W-sh mice, but there were no significant differences in serum levels, except for IP-10. The basal numbers of infiltrating macrophages were also higher in KitW-sh/W-sh mice than in WT mice. After DENV infection, the numbers of infiltrating macrophages were significantly increased in KitW-sh/W-sh mice. In summary, compared to WT mice, KitW-sh/W-sh mice show enhanced sensitivity to DENV and resultant inflammatory and vascular responses.