Effector CD8 T Cell-Dependent Zika Virus Control in the CNS: A Matter of Time and Numbers

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, came into the spotlight in 2016 when it was found to be associated with an increased rate of microcephalic newborns in Brazil. The virus has further been recognized to cause neurologic complications in children and adults in the form of myelitis, encephalitis, acute disseminated encephalomyelitis (ADEM) and Guillain Barre Syndrome in a fraction of infected individuals. With the ultimate goal of identifying correlates of protection to guide the design of an effective vaccine, the study of the immune response to ZIKV infection has become the focus of research worldwide. Both innate and adaptive immune responses seem to be essential for controlling the infection. Induction of sufficient levels of neutralizing antibodies has been strongly correlated with protection against reinfection in various models, while the role of CD8 T cells as antiviral effectors in the CNS has been controversial. In an attempt to improve our understanding regarding the role of ZIKV-induced CD8 T cells in protective immunity inside the CNS, we have expanded on previous studies in intracranially infected mice. In a recent study, we have demonstrated that, peripheral ZIKV infection in adult C57BL/6 mice induces a robust CD8 T cell response that peaks within a week. In the present study, we used B cell deficient as well as wild-type mice to show that there is a race between CXCR3-dependent recruitment of the effector CD8 T cells and local ZIKV replication, and that CD8 T cells are capable of local viral control if they arrive in the brain early after viral invasion, in appropriate numbers and differentiation state. Our data highlight the benefits of considering this subset when designing vaccines against Zika virus.

The combined vaccination protocol of DNA/MVA expressing Zika virus structural proteins as efficient inducer of T and B cell immune responses

“…Heterologous prime/boost immunization in mice with DNA-ZIKV followed by MVA-ZIKV increases the magnitude of adaptive ZIKV-specific CD4 + and CD8 + T cell immune responses. Cellular immune responses are pivotal for protection against ZIKV infection [ 37 , 38 ]. Thus, the ZIKV-specific immunogenicity elicited in mice by DNA-ZIKV or MVA-ZIKV vaccine candidates expressing ZIKV prM-E proteins was examined following homologous or heterologous prime/boost immunizations.…”

“…Heterologous DNA-ZIKV/MVA-ZIKV prime/boost immunization maintains higher magnitude of memory ZIKV-specific CD4 + and CD8 + T cell immune responses than the homologous vector combinations. Memory cellular immune responses are also important for protection against ZIKV infection [ 38 ]. Thus, next we analysed at 53 days post-boost the ZIKV-specific CD4 + and CD8 + T cell memory immune responses induced in mice by the different immunization groups.…”

“…On the other hand, recent studies have confirmed the importance of CD8 + T cells in ZIKV infection and in vaccine-induced protection [ 51 , 53 , 54 ]. Furthermore, in a ZIKV infection model it has been described that CD8 + T cells are capable of local viral control if they arrive in the brain early after viral invasion, demonstrating the benefits of considering this subset when designing vaccines against ZIKV virus [ 38 ]. Our work, demonstrates that a combined immunization with DNA-ZIKV/MVA-ZIKV was able to enhance significantly the levels of adaptive and memory ZIKV-specific CD8 + T cell responses expressing important cytokines as IFN-γ, TNF-α, IL-2 and the degranulation marker CD107a.…”

“…Cellular immune responses are pivotal for protection against ZIKV infection [37,38]. Thus, the ZIKV-specific immunogenicity elicited in mice by DNA-ZIKV or MVA-ZIKV vaccine candidates expressing ZIKV prM-E proteins was examined following homologous or heterologous prime/boost immunizations.…”

“…Memory cellular immune responses are also important for protection against ZIKV infection [38]. Thus, next we analyzed at 53 days post-boost the ZIKV-specific CD4 + and CD8 + T cell memory immune responses induced in mice by the different immunization groups.…”