Background & Aims

Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; nonsecretors (FUT2^-/-) express a limited array of HBGAs. Thus, nonsecretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. Because future human norovirus vaccines will comprise GII.4 antigen and because secretor phenotype impacts GII.4 infection and immunity, nonsecretors may mimic young children immunologically in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure.

Methods

By using specimens collected from the first characterized nonsecretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serologic immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry.

Results

GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes, and dendritic cells, and for 180 days for blocking antibody. Multiple cellular lineages expressing interferon-γ and tumor necrosis factor-α dominated the response. Both T-cell and B-cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to nonsecretor HBGAs.

Conclusions

These data support development of within-genogroup, cross-reactive antibody and T-cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses after GII.4 vaccination in individuals with limited GII.4 immunity, including young children.

中文翻译：

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非分泌者和人类诺如病毒之间的病毒-宿主相互作用。

 背景与目标

人类诺如病毒感染是急性胃肠炎的主要原因。由FUT2基因（分泌酶）介导的遗传多态性决定了菌株的易感性。分泌者在粘膜细胞上表达多种岩藻糖基化组织血型抗原碳水化合物 (HBGA)；非分泌者 ( FUT2 ^-/- ) 表达有限的 HBGA 阵列。因此，非分泌者的诺如病毒株感染多样性较差，包括对流行病学上占主导地位的 GII.4 株的耐药性。由于未来的人类诺如病毒疫苗将包含 GII.4 抗原，并且由于分泌者表型影响 GII.4 感染和免疫力，非分泌者可能会模仿幼儿对 GII.4 疫苗接种的免疫反应，从而为研究交叉保护提供了所需的模型有限的预曝光。

 方法

通过使用从自然感染 GII.2 人诺如病毒的第一个特征性非分泌者队列中收集的样本，我们通过替代中和测定评估了血清免疫的广度，并通过流式细胞术评估了细胞活化和细胞因子产生。

 结果

GII.2感染导致广泛的抗体和细胞免疫激活，对于T细胞、单核细胞和树突细胞来说，持续至少30天，对于封闭抗体来说，持续180天。表达干扰素-γ 和肿瘤坏死因子-α 的多种细胞谱系主导了反应。 T 细胞和 B 细胞反应均与其他 GII 菌株发生交叉反应，但与 GI 菌株无关。为了促进进入机制，胆汁酸的包含对于 GII.2 与非分泌者 HBGA 的结合至关重要。

 结论

这些数据支持基因组内交叉反应抗体和 T 细胞免疫的发展，这些关键结果可能为在 GII.4 免疫力有限的个体（包括幼儿）接种 GII.4 疫苗后引发广泛的免疫反应奠定基础。