Identification of immune and viral correlates of norovirus protective immunity through comparative study of intra-cluster norovirus strains.
Identification of immune and viral correlates of norovirus protective immunity through comparative study of intra-cluster norovirus strains.
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DOI：
10.1371/journal.ppat.1003592
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Karst SM
中科院分区：
文献类型：
--
作者：
Zhu S;Regev D;Watanabe M;Hickman D;Moussatche N;Jesus DM;Kahan SM;Napthine S;Brierley I;Hunter RN 3rd;Devabhaktuni D;Jones MK;Karst SM
原发性诺如病毒感染是否诱导保护性免疫已经成为一个有争议的问题，可能会被来自遗传上不同的诺如病毒株的数据比较所混淆。用诺如病毒阳性接种物进行的早期人类志愿者研究最初得出的结论是，原发性感染不会产生长期的保护性免疫。然而，最近，诺如病毒大流行的流行病学模式已经导致推断原发性诺如病毒感染诱导群体免疫。虽然这些观察结果看似不一致，但实际上可能反映了保护性免疫诱导中病毒株、簇或基因组特异性差异。在这里，我们报告了高度遗传相关的簇内鼠诺如病毒株在诱导保护性免疫应答的能力方面存在显着差异：原发性MNV-3感染诱导了强大的交叉反应性保护，而原发性MNV-1感染诱导了适度的同型保护，没有异型保护。除了这一基本观察，集群内诺如病毒株显示显着差异，在保护性免疫诱导，我们报告了三个额外的重要观察有关诺如病毒：宿主相互作用。首先，抗体和CD 4 + T细胞对于控制继发性诺如病毒感染至关重要。其次，病毒次要结构蛋白VP 2以病毒株特异性方式调节抗原呈递细胞的成熟和保护性免疫诱导，指出MNV-1可能阻止记忆免疫应答刺激的机制。第三，VF 1介导的细胞因子诱导调节也与保护性免疫诱导相关。因此，两种高度遗传相关的诺如病毒株在诱导保护性免疫应答方面显示出显著差异，这强烈表明诺如病毒免疫和疫苗研究的解释必须考虑潜在的病毒株特异性效应。此外，我们已经确定了免疫（抗体和CD 4 + T细胞）和病毒（VP 2和可能的VF 1）相关的诺如病毒保护性免疫。这些发现对于我们理解原发感染期间的诺如病毒免疫以及开发新的诺如病毒疫苗具有重要意义。人类诺如病毒是全球胃肠炎爆发的重要原因，并且可能是严重儿童腹泻的主要原因。有效的诺如病毒疫苗将对人类健康产生重大影响，但无疑会受到几个障碍的困扰。首先，诺如病毒属在遗传上和潜在的抗原性上是高度多样的。其次，目前尚不清楚人诺如病毒在自然感染后是否引起持久的保护性免疫。在这里，我们测试的假设，诺如病毒显示病毒株特异性的差异，在他们的保护性免疫刺激。事实上，我们的研究结果表明，两种高度遗传相关的鼠诺如病毒株在刺激保护性免疫应答方面存在显着差异。此外，我们证明了抗体和CD 4 + T细胞对于保护免受继发性诺如病毒感染是绝对必要的。最后，我们揭示了保护性免疫诱导的两种病毒相关性--VF 1介导的细胞因子拮抗作用和VP 2依赖的抗原呈递细胞成熟抑制作用。总的来说，这些信息不仅为关于人诺如病毒保护性免疫的看似不一致的结果提供了潜在的解释，而且还揭示了开发有效的人诺如病毒疫苗的先前未被认识到的复杂性-单个病毒株在与宿主免疫系统的相互作用方面可能存在显著差异，因此在其免疫原性方面也存在显著差异。
Whether or not primary norovirus infections induce protective immunity has become a controversial issue, potentially confounded by the comparison of data from genetically distinct norovirus strains. Early human volunteer studies performed with a norovirus-positive inoculum initially led to the conclusion that primary infection does not generate long-term, protective immunity. More recently though, the epidemiological pattern of norovirus pandemics has led to the extrapolation that primary norovirus infection induces herd immunity. While these are seemingly discordant observations, they may in fact reflect virus strain-, cluster-, or genogroup-specific differences in protective immunity induction. Here, we report that highly genetically related intra-cluster murine norovirus strains differ dramatically in their ability to induce a protective immune response: Primary MNV-3 infection induced robust and cross-reactive protection, whereas primary MNV-1 infection induced modest homotypic and no heterotypic protection. In addition to this fundamental observation that intra-cluster norovirus strains display remarkable differences in protective immunity induction, we report three additional important observations relevant to norovirus:host interactions. First, antibody and CD4+ T cells are essential to controlling secondary norovirus infections. Second, the viral minor structural protein VP2 regulates the maturation of antigen presenting cells and protective immunity induction in a virus strain-specific manner, pointing to a mechanism by which MNV-1 may prevent the stimulation of memory immune responses. Third, VF1-mediated regulation of cytokine induction also correlates with protective immunity induction. Thus, two highly genetically-related norovirus strains displayed striking differences in induction of protective immune responses, strongly suggesting that the interpretation of norovirus immunity and vaccine studies must consider potential virus strain-specific effects. Moreover, we have identified immune (antibody and CD4+ T cells) and viral (VP2 and possibly VF1) correlates of norovirus protective immunity. These findings have significant implications for our understanding of norovirus immunity during primary infections as well as the development of new norovirus vaccines. Human noroviruses are a significant cause of gastroenteritis outbreaks worldwide and likely the leading cause of severe childhood diarrhea. An efficacious norovirus vaccine would have a major impact on human health but will undoubtedly be confounded by several roadblocks. First, the norovirus genus is highly genetically, and potentially antigenically, diverse. Second, it is currently unclear whether human noroviruses elicit lasting protective immunity upon natural infection. Here, we test the hypothesis that noroviruses display virus strain-specific differences in their stimulation of protective immunity. Indeed, our results reveal that two highly genetically related murine norovirus strains differ dramatically in their stimulation of protective immune responses. Moreover, we demonstrate that antibody and CD4+ T cells are absolutely essential to protecting from a secondary norovirus infection. Finally, we have revealed two viral correlates of protective immunity induction – VF1-mediated cytokine antagonism and VP2-dependent inhibition of antigen presenting cell maturation. Collectively, this information not only offers a potential explanation for the seemingly discordant results regarding human norovirus protective immunity but it also brings to light a previously unrecognized complexity in developing an efficacious human norovirus vaccine – individual virus strains may differ significantly in their interactions with the host immune system and thus in their immunogenicity.
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影响因子：
5.4
作者：
Changotra, Harish;Jia, Yali;Karst, Stephanie M.
通讯作者：
Karst, Stephanie M.
影响因子：
5.4
作者：
Farkas, Tibor;Sestak, Karol;Jiang, Xi
通讯作者：
Jiang, Xi
影响因子：
56.9
作者：
Karst, SM;Wobus, CE;Virgin, HW
通讯作者：
Virgin, HW
统一的诺如病毒术语和基因分型的提案。
影响因子：
2.7
作者：
Kroneman A;Vega E;Vennema H;Vinjé J;White PA;Hansman G;Green K;Martella V;Katayama K;Koopmans M
通讯作者：
Koopmans M
影响因子：
64.8
作者：
Esplugues, Enric;Huber, Samuel;Gagliani, Nicola;Hauser, Anja E.;Town, Terrence;Wan, Yisong Y.;O'Connor, William, Jr.;Rongvaux, Anthony;Van Rooijen, Nico;Haberman, Ann M.;Iwakura, Yoichiro;Kuchroo, Vijay K.;Kolls, Jay K.;Bluestone, Jeffrey A.;Herold, Kevan C.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.