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New mouse model joins the fight against Zika

Although the worst of the global Zika virus outbreak may be over, we still don't know why the virus persists in certain tissues after the infection has cleared. Or how the immune system counteracts the virus to protect against re-infection? Or, how to determine the chance of long-term complications?

New research from La Jolla Institute for Allergy and Immunology (LJI) has analyzed how Zika interacts with its host to cause disease by pinpointing CD8+ T cells. These cells are a subset of T cells and are more commonly known as cytotoxic or killer T cells that destroy virus filled cells. They are important gatekeepers controlling Zika to limit the severity of the disease.

Their findings map the structural landmarks — or epitopes, part of an antigen molecule which an antibody attaches to — recognized by CD8+ cells. The paper appears in the January 12, 2017, issue of Cell Host & Microbe. Epitopes provide an important tool to track Zika-specific T cells in the context of different disease models.

"Our study acknowledges the importance of T cells in an environment where most people are focused on antibodies.

"For most diseases a strong antibody response is enough. But with Zika and dengue viruses, a phenomenon known as antibody-dependent enhancementis a concern, which makes a strong T cell response really important."

Sujan Shresta PhD, Associate Professor, Center for Infectious Disease, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA and the study's senior author.

For some viruses fighting off an infection becomes easier if the immune system has previously encountered a closely related virus, and successfully produced antibodies against that. As in the case for influenza or flu.

Dengue is a different story altogether.

While infection with one type of dengue will provide lifelong protection against that type, any pre-existing antibodies increase the risk for severe disease during a second infection with a new type. There are at least four types of dengue known as serotypes.

Antibody-dependent enhanced reaction is of concern as both dengue and Zika are closely related and may react similarly.

Previous studies have suggested an important role for T cells during dengue infections. Shresta and her team wondered whether the same was true for Zika.

To investigate the role of CD8+ T cells during primary Zika infections, Annie Elong Ngono PhD, blocked the receptor for interferon 1 (IFNAR) with IFNAR-blocking antibodies. This makes mice as the model animal used for experimentation, more susceptible to infection by Zika. Then she analyzed T cells isolated from Zika-infected mice, mapping which viral portions got a strong immune response. She confirmed her results by replicating her experiments in T cell-competent mice to find both mouse models had a robust CD8+ T cell response to Zika.

Results establish a new mouse model for Zika that can be used to study Zika-specific T cell responses, for testing vaccines, and for antiviral candidates.

The new mouse model will also help explain how Zika causes neurological conditions such as Guillain-Barré syndrome, a type of temporary paralysis, and brain inflammation (encephalitis) in some adults. Or, how Zika finds its way into tears, saliva and semen, in some cases managing to stay there for months.

"Being able to track Zika-specific T cells across different model systems provides a valuable tool to better understand sexual and trans-placental transmission and how the virus crosses the blood-brain barrier to reach other immune-privileged areas such the eye and eventually the testes."

Annie Elong Ngono PhD, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA, and first author on the study.

Abstract Highlights
•LysMCre+IFNARfl/fl mice developed as a model to investigate T cell responses to ZIKV
•ZIKV infection elicits CD8+ T cells targeting viral PrM, E, and NS5 proteins in mice
•ZIKV-immune CD8+ T cell transfer reduced while depletion increased viral burdens in mice
•CD8−/− mice displayed higher mortality with ZIKV infection

CD8+ T cells may play a dual role in protection against and pathogenesis of flaviviruses, including Zika virus (ZIKV). We evaluated the CD8+ T cell response in ZIKV-infected LysMCre+IFNARfl/fl C57BL/6 (H-2b) mice lacking the type I interferon receptor in a subset of myeloid cells. In total, 26 and 15 CD8+ T cell-reactive peptides for ZIKV African (MR766) and Asian (FSS13025) lineage strains, respectively, were identified and validated. CD8+ T cells from infected mice were polyfunctional and mediated cytotoxicity. Adoptive transfer of ZIKV-immune CD8+ T cells reduced viral burdens, whereas their depletion led to higher tissue burdens, and CD8−/− mice displayed higher mortality with ZIKV infection. Collectively, these results demonstrate that CD8+ T cells protect against ZIKV infection. Further, this study provides a T cell competent mouse model for investigating ZIKV-specific T cell responses.

Zika virus, CD8+ T cell, epitope, peptide, mouse model, LysMCre+IFNARfl/fl

Full citation: "Mapping and Role of CD8+ T Cell Response During Primary Zika Infection in Mice." Annie Elong Ngono, Edward Vizcarra, William Tang, Nicholas Sheets, Yunichel Joo, Kenneth Kim, Matthew J. Gorman, Michael S. Diamond and Sujan Shresta. 2016. Cell Host & Microbe. DOI: 10.1016/j.chom.2016.12.010

The research was funded by NIAID/NIH grants (R01 AI116813 and R01 AI073755 and R01 AI104972 and the La Jolla Institute for Allergy and Immunology.

About La Jolla Institute
La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.

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CD8+ T cells during primary Zika infections, are blocked by the receptor for interferon
-blocking antibodies thus making a model animal for ZIKA study.
Image Credit: La Jolla Institute for Allergy and Immunology



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