Study on the effects of dengue virus nonstructural protein 1-induced antibodies on plasminogen activation

Abstract

Dengue virus (DENV) is a mosquito-transmitted virus which infects humans might cause flu-like illness called dengue fever (DF) or lead to potentially lethal diseases like dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks associated with DHF/DSS patients However the mechanism to cause hemorrhage in DHF/DSS is still not fully understood DENV nonstructural protein 1 (NS1) is secreted early during infection and is believed to be involved in DENV pathogenesis through molecular mimicry In previous study we found anti-thrombin antibodies in dengue patients which can recognize NS1 contain both anti-thrombotic and pro-fibrinolytic activities However it is unclear whether these antibodies are indeed induced by DENV NS1 Thus we immunized both mice and rabbits with recombinant NS1 to test whether NS1 can induce coagulation factor-cross-reactive antibodies Results from both NS1 hyper-immunized mice and rabbits sera indicated the presence of antibodies that can bind to thrombin and plasminogen (Plg) To study the effects of these NS1-induced autoantibodies on coagulation and fibrinolysis we generated several Plg cross-reactive anti-NS1 monoclonal antibodies (mAbs) and found some of these mAbs were endowed with serine protease activity and could enhance Plg conversion to plasmin In addition the results of epitope mapping revealed that mAb 2A5 could recognize NS1 C-terminal residues 305-311 and probably cross-react with Plg on region 609-616 Taken together these results suggest that DENV NS1-induced antibodies cross-react with Plg may enhance Plg conversion to plasmin and contribute to hyper-fibrinolysis In vaccine design the epitopes recognized by these NS1-induced Plg cross-reactive autoantibodies should be avoided to prevent possible side effects

Date of Award	2014 Jul 26
Original language	English
Supervisor	Trai-Ming Yeh (Supervisor)