Antibodies are not required to a protective immune response against dengue virus elicited in a mouse encephalitis model

Abstract

Generating neutralizing antibodies have been considered a prerequisite to control dengue virus (DENV) infection. However, T lymphocytes have also been shown to be important in a protective immune state. In order to investigate the contribution of both humoral and cellular immune responses in DENV immunity, we used an experimental model in which a non-lethal DENV2 strain (ACS46) is used to intracranially prime Balb/C mice which develop protective immunity against a lethal DENV2 strain (JHA1). Primed mice generated envelope-specific antibodies and CD8(+) T cell responses targeting mainly non-structural proteins. Immune sera from protected mice did not confer passive protection to naïve mice challenged with the JHA1 strain. In contrast, depletion of CD4(+) and CD8(+) T lymphocytes significantly reduced survival of ACS46-primed mice challenged with the JHA1 strain. Collectively, results presented in this study show that a cellular immune response targeting non-structural proteins are a promising way in vaccine development against dengue.

Microglia retard dengue virus-induced acute viral encephalitis

“…Infection of neuroadapted DENV can induce systemic immune responses 26 , while CD8-positive CTLs are required for cellular immune defense against systemic DENV infection 27 . Upon viral infection, activated microglial cells are able to process and present endogenous viral epitopes to T cells and competent APCs 28 .…”

“…In another model of DENV-infected encephalitic mice, an increase in the infiltration of CD8-positive T cells accompanied by the presence of IFN-γ was reported; IFN-γ plays a crucial role in protection against DENV infection in mice and protects against initial systemic and subsequent CNS disease 34 . The actual role of CD8-positive CTL responses in the brain after DENV infection has been studied, although depleting CD8-positive cells retards DENV-induced encephalitic lethality 27 . DENV-infected peripheral and systemic dendritic cells trigger antigen presentation to activate CD8-positive CTL responses, which elicit antiviral effects against DENV infection 35 .…”

A Tetravalent Sub-unit Dengue Vaccine Formulated with Ionizable Cationic Lipid Nanoparticle induces Significant Immune Responses in Rodents and Non-Human Primates

“…Generation of nAbs against all four Dengue viruses has been a key objective of current Dengue vaccine candidates 19 . However, emerging evidence suggests that T cell responses are also crucial for protection against Dengue virus infection 43 . Based on our recent discovery that specific ionizable cationic lipid nanoparticles (LNPs) can boost B-cell and T-cell responses to sub-unit antigens, we evaluated a novel tetravalent subunit Dengue virus vaccine formulation containing ionizable cationic LNPs.…”

The Role of Heterotypic DENV-specific CD8+T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection

“…CD8 + T cell depletion prior to infection has been shown to increase viral load in various organs upon infection with DENV-2 in Ifnar −/− mice (Yauch et al, 2009). Similarly, depletion of CD4 + and CD8 + T lymphocytes reduced survival of DENV-2-primed BALB/c mice challenged with a lethal DENV-2 strain (Amorim et al, 2016). In line with these studies, a recent report described that cross-reactive T cells were able to enhance viral clearance in tissues from Ifnar −/− HLA*B0702 transgenic mice despite having lower magnitude and avidity than serotype-specific T cells (Elong Ngono et al, 2016).…”