Research Article: CD4+T cells mediate protection against Zika associated severe disease in a mouse model of infection

Date Published: September 13, 2018

Publisher: Public Library of Science

Author(s): Mariah Hassert, Kyle J. Wolf, Katherine E. Schwetye, Richard J. DiPaolo, James D. Brien, Amelia K. Pinto, Ana Fernandez-Sesma.


Zika virus (ZIKV) has gained worldwide attention since it emerged, and a global effort is underway to understand the correlates of protection and develop diagnostics to identify rates of infection. As new therapeutics and vaccine approaches are evaluated in clinical trials, additional effort is focused on identifying the adaptive immune correlates of protection against ZIKV disease. To aid in this endeavor we have begun to dissect the role of CD4+T cells in the protection against neuroinvasive ZIKV disease. We have identified an important role for CD4+T cells in protection, demonstrating that in the absence of CD4+T cells mice have more severe neurological sequela and significant increases in viral titers in the central nervous system (CNS). The transfer of CD4+T cells from ZIKV immune mice protect type I interferon receptor deficient animals from a lethal challenge; showing that the CD4+T cell response is necessary and sufficient for control of ZIKV disease. Using a peptide library spanning the complete ZIKV polyprotein, we identified both ZIKV-encoded CD4+T cell epitopes that initiate immune responses, and ZIKV specific CD4+T cell receptors that recognize these epitopes. Within the ZIKV antigen-specific TCRβ repertoire, we uncovered a high degree of diversity both in response to a single epitope and among different mice responding to a CD4+T cell epitope. Overall this study identifies a novel role for polyfunctional and polyclonal CD4+T cells in providing protection against ZIKV infection and highlights the need for vaccines to develop robust CD4+T cell responses to prevent ZIKV neuroinvasion and limit replication within the CNS.

Partial Text

As a member of the family Flaviviridae, Zika virus (ZIKV) is related to mosquito spread arboviruses including West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV). While having been identified in 1947 [1], ZIKV first entered the dialogue of emerging pathogens following a large outbreak on Yap island in the Federated States of Micronesia in 2007 [2]. This unexpected emergence of ZIKV beyond its traditional borders and the subsequent global spread of the virus in the last ten years (Reviewed in [3]) has caused a public health emergency. As ZIKV spread, infection has become associated with increased risks for congenital birth defects and neurological disease [4–12]. As it is now recognized that there is an increased risk of severe disease associated with ZIKV infection, focus has shifted toward detection, defining correlates of protection, and the development of a vaccine or antiviral to protect against disease progression.

As we begin to develop a deeper understanding of the correlates of protection against flavivirus disease, we are appreciating that the combination of both the adaptive cellular and humoral responses are required for protection against many flaviviral pathogens. The generation of a strongly neutralizing antibody response has long been the gold standard for immune mechanism that correlate with protection for many infections; however, the role of T cell responses in vaccine mediated protection against viral disease has become clear. For example, the strong and broad T cell response generated by the yellow fever vaccine (YFV-17D) (reviewed in [46]) is thought to contribute to its high efficacy. As with YFV, recent studies have suggested that strong T cell responses may also be important for controlling DENV infections and for reducing the possible effects of antibody dependent enhancement (ADE) [47, 48]. While our understanding of the cellular immune responses that develops during the natural course of flavivirus infection has begun to contribute to our understanding of flavivirus correlates of protection, there are still significant gaps in our knowledge of how to generate a protective immune response against this family of emerging pathogens.