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.
Highlights
The emergence of Zika virus (ZIKV) as a threat to public health in the beginning of the 21st century caught everybody by surprise
Given the neurotropism of ZIKV and the fact that a fraction of postnatal ZIKV infections in humans may result in various forms of neuropathology including fatal encephalitis [9, 10, 28], we found it pertinent to determine whether CD8 T cells could contribute significantly to antiviral protection in the CNS and if that were the case, what are the factors deciding the disease outcome
In light of data suggesting a critical role of IL1 receptor signaling in controlling infection with West Nile virus (WNV) [36,37,38], an emerging flavivirus like ZIKV, we wanted to assess ZIKV disease manifestation and cellular infiltration in the brains of IL-1R1 KO mice
Summary
The emergence of Zika virus (ZIKV) as a threat to public health in the beginning of the 21st century caught everybody by surprise. Zika Virus Control in CNS in 2015 in Brazil, which led the WHO to classify ZIKV as a public health emergency of international concern from February 2016 until November 2016 [3,4,5]. A number of animal models have been developed to study the biology behind ZIKV infection and protection [5, 14, 15]. ZIKV is incapable of blocking the type I IFN response and viral replication following peripheral infection is limited; the initial approach to study the infection in this species was to disrupt the type I IFN signaling pathway by either genetic manipulation or administration of IFNAR blocking Abs prior to infection [16,17,18]. The role of type I IFNs in shaping adaptive immune responses, and in shaping CD8 and CD4 T cell responses [19, 20], highlights the importance of including immunocompetent models to characterize ZIKV-induced T cell responses
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