Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice

Abstract

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection. Previous animal models have primarily focused on pathogenesis in immunocompromised mice. In this study, we provide a model of ZIKV infection in wild-type immunocompetent C57BL/6 mice, and have provided an analysis of the immune response to infection. We evaluated the activation of several innate immune cell types, and studied the kinetics, phenotype, and functionality of T cell responses to ZIKV infection. Our results demonstrate that ZIKV infection is mild in wild-type immunocompetent C57BL/6 mice, resulting in minimal morbidity. Our data establish that at the peak of the adaptive response, antigen-experienced CD4+ T cells polarize to a Th1 phenotype, and antigen-experienced CD8+ T cells exhibit an activated effector phenotype, producing both effector cytokines and cytolytic molecules. Furthermore, we have identified a novel ZIKV CD8+ T cell epitope in the envelope protein that is recognized by the majority of responding cells. Our model provides an important reference point that will help dissect the impact of polymorphisms in the circulating ZIKV strains on the immune response and ZIKV pathogenesis. In addition, the identification of a ZIKV epitope will allow for the design of tetramers to study epitope-specific T cell responses, and will have important implications for the design and development of ZIKV vaccine strategies.

CD8 + T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

“…Of these six peptides (Table 1), the epitope E 4 -12 induced the highest IFN-␥-producing cells (i.e., 3 to 4% IFN-␥ ϩ CD8 ϩ cells after ZIKV infection), suggesting the immunodominance of E 4 -12 epitope among positive peptides we identified. This finding was also consistent with Pardy's report that the E 4 -12 epitope was recognized by a majority of responding cells during ZIKV infection (9). Two peptides derived from the E protein (E 4 -12 and E 310 -317 ) and one from NS2A (NS2A 91-98 ) of our virus strain are consistent with a recent report (5).…”

“…These models are sufficient for characterizing infection and the pathogenesis of the virus because a clear infection phenotype is observed, but they are unable to provide a comprehensive and accurate understanding of the natural immune response to ZIKV infection. Recently, two reports indicated that ZIKV can infect WT mice and activate CD8 ϩ T cells (8,9). Our studies extended these findings by characterizing the immune response to ZIKV more comprehensively in the key peripheral organs of WT adult mice.…”

“…WT mice treated with IFNAR-blocking antibody or mice genetically deficient in IFNAR are currently popular animal models for investigating the immune response and pathogenesis of ZIKV infection (5, 6), although two papers reported recently that CD8 ϩ T cells could be activated by ZIKV infection in B6 WT mice (8,9). Numerous studies have demonstrated that type I interferon (IFN) deficiency impaired the CD8 ϩ T cell response during virus infection through many cellular and molecule mechanisms, such as by impairing the priming effect of dendritic cells and upregulating the expression of the inhibitory molecules PD-1 and Tim3 of CD8 ϩ T cells during virus infection (10,12,13).…”

“…However, the immune systems of these mice are underdeveloped, which means that these mice are also immunocompromised (7). Recently, two additional groups demonstrated that CD8 ϩ T cells can be activated by ZIKV infection in WT mice (8,9). However, the function of WT CD8 ϩ T cells was not addressed in these two reports, and whether memory CD8 ϩ T cells are generated in WT mice during ZIKV infection has never been reported.…”

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

“…Indeed, several works have already investigated the recognition of Zika virus by T cells (57,58), and others have shown that Zika virus infection can induce type I IFNs and downstream interferon-stimulated genes (ISGs). Zika virus infection of human skin fibroblasts induced the transcription of Toll-like receptor 3 (TLR3), RIGI, and MDA5, as well as other ISGs, such as OAS2, ISG15, and MX1 (59).…”