Studies on the cellular immune responses induced by chimeric dengue virus nonstructural protein 1-encapsulated nanocomplexes

Abstract

Based on WHO report over 2 5 billion people are now at risk from dengue virus (DENV) and there are approximately 390 million DENV infections worldwide every year However there is still no approved antiviral treatment or vaccine available Our previous studies showed that the C-terminal region of DENV nonstructural protein 1 (NS1) is responsible for molecular mimicry that causes anti-DENV NS1 antibody-mediated endothelial cell apoptosis and platelet dysfunction Therefore we have generated a chimeric NS1 protein which consists of N-terminal region of DENV NS1 (amino acids 1-270) and C-terminal region of Japanese encephalitis virus NS1 (amino acids 271-352) called DJ NS1 as a potential candidate for DENV vaccine Our previous studies showed that active immunization with DJ NS1-encapsulated nanocomplexes not only induced higher anti-DJ NS1 antibody titers than DJ NS1 plus alum but also significantly decreased the DENV-induced prolonged bleeding time in the mouse model DJ NS1-encapsulated nanocomplexes induced longer antibody persistence and provided long-term protection Besides humoral immune responses in the present study we further investigated whether DJ NS1-encapsulated nanocomplexes can also induce cellular immune responses Polymer-based nanocomplexes as adjuvant induce dendritic cell (DC) activation both in vitro and in vivo and better antigen uptake than alum in vitro In the mouse model mice immunized with DJ NS1-encapsulated nanocomplexes induced better lymphocyte proliferation and T cell activation than alum in response to DJ NS1 antigen In addition DJ NS1-encapsulated nanocomplexes induced both Th1/Th2 responses as determined by cytokine production Moreover mice immunized with DJ NS1-encapsulated nanocomplexes induced NS1-specific CD8+ T cell cytotoxicity while NS1-specific CD8+ T cells caused only a minor effect on DENV-induced prolonged bleeding time Furthermore DJ NS1-encapsulated nanocomplexes induced DC and T cell long-lasting activation better than alum Taken together DJ NS1-encapsulated nanocomplexes induce both humoral and cellular immune responses which provide a potential vaccine candidate against DENV

Date of Award	2015 Aug 26
Original language	English
Supervisor	Yee-Shin Lin (Supervisor)