CD4+T cells mediate protection against Zika associated severe disease in a mouse model of infection.
CD4+T cells mediate protection against Zika associated severe disease in a mouse model of infection.
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DOI：
10.1371/journal.ppat.1007237
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Pinto AK
中科院分区：
文献类型：
--
作者：
Hassert M;Wolf KJ;Schwetye KE;DiPaolo RJ;Brien JD;Pinto AK
寨卡病毒（ZIKV）自出现以来已引起全世界的关注，全球正在努力了解保护的相关性并开发诊断方法以确定感染率。随着新的治疗方法和疫苗方法在临床试验中进行评估，额外的努力集中在识别针对ZIKV疾病的保护的适应性免疫相关性上。为了帮助这一奋进，我们已经开始剖析CD 4 +T细胞在预防神经侵袭性ZIKV疾病中的作用。我们已经确定了CD 4 +T细胞在保护中的重要作用，证明在缺乏CD 4 +T细胞的情况下，小鼠具有更严重的神经系统后遗症和中枢神经系统（CNS）中病毒滴度的显著增加。来自ZIKV免疫小鼠的CD 4 +T细胞的转移保护I型干扰素受体缺陷型动物免受致死性攻击;表明CD 4 +T细胞应答对于控制ZIKV疾病是必要且足够的。使用跨越完整ZIKV多蛋白的肽文库，我们鉴定了启动免疫应答的ZIKV编码的CD 4 +T细胞表位和识别这些表位的ZIKV特异性CD 4 +T细胞受体。在ZIKV抗原特异性TCRβ库中，我们发现了响应于单个表位和响应于CD 4 +T细胞表位的不同小鼠之间的高度多样性。总的来说，本研究鉴定了多功能和多克隆CD 4 +T细胞在提供针对ZIKV感染的保护中的新作用，并强调了对疫苗的需求，以产生稳健的CD 4 +T细胞应答，以防止ZIKV神经侵袭并限制CNS内的复制。自2015年在美洲检测到ZIKV以来，已经做出紧急努力来开发ZIKV特异性诊断方法和新型疫苗。然而，我们评估ZIKV特异性免疫应答的有限手段阻碍了对感染的自然史、与其他虫媒病毒的相互作用以及由治疗剂或疫苗接种介导的保护的充分理解。在这项研究中，我们使用小鼠感染模型研究了CD 4 +T细胞在保护免受ZIKV感染中的作用。我们发现，CD 4 +T细胞对于保护免受ZIKV严重疾病是必要的和足够的。我们已经鉴定了在感染期间靶向的ZIKV编码的CD 4 +T细胞表位和这些表位的同源T细胞受体。该研究强调了开发ZIKV疫苗的需要，所述ZIKV疫苗引发强烈的CD 4 +T细胞应答以潜在地提供针对ZIKV神经侵袭和CNS中复制的保护。
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. Since the detection of ZIKV in the Americas in 2015, urgent efforts have been made to develop ZIKV-specific methods of diagnosis and novel vaccines. However, a full understanding of the natural history of infection, interactions with other arboviruses, and the protection mediated by therapeutics or vaccination is hindered by our limited means of assessing ZIKV-specific immune responses. In this study, we investigated the role of CD4+T cells in protection from ZIKV using a mouse model of infection. We found that CD4+T cells are both necessary and sufficient for protection from ZIKV severe disease. We have identified the ZIKV-encoded CD4+T cell epitopes which are targeted during infection and the cognate T cell receptors to these epitopes. This study underscores the need to develop ZIKV vaccines which elicit strong CD4+T cell responses to potentially provide protection from ZIKV neuroinvasion and replication in the CNS.
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影响因子：
30.5
作者：
Dejnirattisai W;Supasa P;Wongwiwat W;Rouvinski A;Barba-Spaeth G;Duangchinda T;Sakuntabhai A;Cao-Lormeau VM;Malasit P;Rey FA;Mongkolsapaya J;Screaton GR
通讯作者：
Screaton GR
影响因子：
4.6
作者：
Cimini, Eleonora;Castilletti, Concetta;Agrati, Chiara
通讯作者：
Agrati, Chiara
影响因子：
4.4
作者：
Charini, WA;Kuroda, MJ;Letvin, NL
通讯作者：
Letvin, NL
影响因子：
3.8
作者：
Brasil P;Calvet GA;Siqueira AM;Wakimoto M;de Sequeira PC;Nobre A;Quintana Mde S;Mendonça MC;Lupi O;de Souza RV;Romero C;Zogbi H;Bressan Cda S;Alves SS;Lourenço-de-Oliveira R;Nogueira RM;Carvalho MS;de Filippis AM;Jaenisch T
通讯作者：
Jaenisch T
DOI：
10.1016/0035-9203(52)90042-4
发表时间：
1952-01-01
影响因子：
2.2
作者：
DICK, GWA;KITCHEN, SF;HADDOW, AJ
通讯作者：
HADDOW, AJ