Protection from Secondary Dengue Virus Infection in a Mouse Model Reveals the Role of Serotype Cross-reactive B and T cells

摘要

The four dengue virus (DENV) serotypes cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome. Although severe disease has been associated with heterotypic secondary DENV infection, most secondary DENV infections are asymptomatic or result in classic DF. The role of cross-reactive immunity in mediating cross-protection against secondary heterotypic DENV infection is not well-understood. DENV infection of interferon-α/β and -γ receptor-deficient (AG129) mice reproduces key features of human disease. We previously demonstrated a role in cross-protection for pre-existing cross-reactive antibodies, maintained by long-lived plasma cells (LLPCs). Here we use a sequential infection model, infecting AG129 mice with DENV-1 followed by DENV-2 6–8 weeks later. We find that increased DENV-specific avidity during acute secondary heterotypic infection is mediated by cross-reactive memory B cells, as evidenced by increased numbers of DENV-1-specific cells by ELISPOT and higher avidity against DENV-1 of supernatants from polyclonally-stimulated splenocytes isolated from mice experiencing secondary DENV-2 infection. However, increased DENV-specific avidity is not associated with increased DENV-specific neutralization, which appears to be mediated by naïve B cells. Adoptive transfer of DENV-1-immune B and T cells into naïve mice prior to secondary DENV-2 infection delayed mortality. Mice depleted of T cells developed signs of disease but recovered after secondary DENV infection. Overall, we found that protective cross-reactive antibodies are secreted by both LLPCs and memory B cells and that both cross-reactive B cells and T cells provide protection against a secondary heterotypic DENV infection. Understanding the protective immunity that develops naturally against DENV infection may help design future vaccines.