Date Published: February 23, 2017
Publisher: Public Library of Science
Author(s): Ryan D. Pardy, Maaran M. Rajah, Stephanie A. Condotta, Nathan G. Taylor, Selena M. Sagan, Martin J. Richer, Andrea J. Sant.
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.
Zika virus (ZIKV) is an emerging mosquito-borne pathogen that belongs to the flavivirus genus of the Flaviviridae family, and is related to other globally relevant human pathogens including Dengue, West Nile and Yellow Fever viruses. ZIKV was first described in 1947 after it was isolated from a febrile sentinel monkey in the Zika forest region of Uganda [1, 2]. Although human infection was reported as early as 1964, the first major ZIKV outbreak did not occur until 2007, when nearly 75% of the population of Yap Island, Federated States of Micronesia became infected in a period of 4 months [3–5]. This was followed by an outbreak in French Polynesia in 2013, which marked the first reports of infection-associated neurological symptoms such as Guillain-Barré syndrome and fetal microcephaly [4, 5]. The current ongoing pandemic in the Americas has already seen millions of people infected, and an alarming increase in cases of fetal microcephaly in babies born to mothers infected during pregnancy [4, 5]. Furthermore, the mounting evidence linking ZIKV infection to birth defects has been deemed sufficient to establish a causal relationship . This includes the attenuation of human neural progenitor cell growth in vitro, detection of ZIKV in the blood and tissues of microcephalic fetuses, the detection of ZIKV-specific IgM antibodies in the cerebrospinal fluid of microcephalic infants, and intrauterine growth restriction and microcephaly in fetuses of pregnant SJL mice infected with a Brazilian ZIKV isolate [7–10]. Thus, due to the magnitude of the current pandemic and the increase in fetal microcephaly associated with infection, there is an urgent need to develop experimental models for ZIKV to understand infection, tissue tropism, pathogenesis, and the immune response.
A rapid and effective global response will be required for the development of vaccines and antiviral therapies to combat the ongoing ZIKV epidemic in the Americas where viral pathogenesis appears to be increasing in severity. Paramount to this goal is the establishment of suitable small animal models to study ZIKV pathogenesis and the immune response to infection. Despite the development of several small animal models to study ZIKV infection and pathogenesis, most of these models lack critical innate immune components and succumb rapidly to ZIKV infection, precluding an analysis of the immune response to infection [11–14, 16, 17]. As such, the model developed and data presented herein represent an important reference point for the analysis of the immune response to ZIKV infection in adult, immunocompetent mice, and has uncovered a novel epitope of ZIKV recognized by CD8+ T cells.