Purpose

Zika (ZIKV) is a viral inflammatory disease affecting adults, children, and developing fetuses. It is endemic to tropical and sub-tropical countries, resulting in half the global population at risk of infection. Despite this, there are no approved therapies or vaccines against ZIKV disease. Non-invasive imaging biomarkers are potentially valuable tools for studying viral pathogenesis, prognosticating host response to disease, and evaluating in vivo efficacy of experimental therapeutic interventions. In this study, we evaluated [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG)-positron emission tomography (PET) as an imaging biomarker of ZIKV disease in a mouse model and correlated metabolic tracer tissue uptake with real-time biochemical, virological, and inflammatory features of tissue infection.

Methods

[¹⁸F]FDG-PET/CT imaging was performed in an acute, lethal ZIKV mouse infection model, at increasing stages of disease severity. [¹⁸F]FDG-PET findings were corroborated with ex vivo wholemount-tissue autoradiography and tracer biodistribution studies. Tracer uptake was also correlated with in situ tissue disease status, including viral burden and inflammatory response. Immune profiling of the spleen by flow cytometry was performed to identify the immune cell subsets driving tissue pathology and enhancing tracer uptake in ZIKV disease.

Results

Foci of increased [¹⁸F]FDG uptake were consistently detected in lymphoid tissues—particularly the spleen—of ZIKV-infected animals. Splenic uptake increased with disease severity, and corroborated findings in tissue pathology. Increased splenic uptake also correlated with increased viral replication and elevated expression of pro-inflammatory cytokines within these tissues. ZIKV-infected spleens were characterized by increased infiltration of myeloid cells, as well as increased proliferation of both myeloid and lymphoid cells. The increased cell proliferation correlated with increased tracer uptake in the spleen. Our findings support the use of [¹⁸F]FDG as an imaging biomarker to detect and track ZIKV disease in real time and highlight the dependency of affected tissue on the nature of the viral infection.

Conclusion

[¹⁸F]FDG uptake in the spleen is a useful surrogate for interrogating in situ tissue viral burden and inflammation status in this ZIKV murine model.

中文翻译：

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[18F]FDG-PET 作为寨卡病毒感染淋巴组织疾病和炎症生物标志物的临床前评估

目的

寨卡病毒 (ZIKV) 是一种影响成人、儿童和发育中胎儿的病毒性炎症性疾病。它流行于热带和亚热带国家，导致全球一半人口面临感染风险。尽管如此，尚无针对 ZIKV 疾病的获批疗法或疫苗。非侵入性成像生物标志物是研究病毒发病机制、预测宿主对疾病的反应以及评估实验性治疗干预的体内疗效的潜在有价值的工具。在这项研究中，我们评估了 [ ¹⁸ F] 氟脱氧葡萄糖 ([ ¹⁸ F]FDG)-正电子发射断层扫描 (PET) 作为 ZIKV 疾病在小鼠模型中的成像生物标志物，并将代谢示踪剂组织摄取与实时生化、病毒学、和组织感染的炎症特征。

方法

[ ¹⁸ F]FDG-PET/CT 成像是在急性、致命的 ZIKV 小鼠感染模型中进行的，处于疾病严重程度的增加阶段。[ ¹⁸ F]FDG-PET 结果得到了离体全组织放射自显影和示踪剂生物分布研究的证实。示踪剂摄取也与原位组织疾病状态相关，包括病毒负荷和炎症反应。通过流式细胞术对脾脏进行免疫分析，以确定驱动组织病理学和增强 ZIKV 疾病中示踪剂摄取的免疫细胞亚群。

结果

在 ZIKV 感染动物的淋巴组织（尤其是脾脏）中始终检测到[ ^{18 F]FDG 摄取增加的病灶。}脾脏摄取随着疾病的严重程度而增加，并证实了组织病理学的发现。脾脏摄取增加也与病毒复制增加和这些组织内促炎细胞因子表达升高有关。ZIKV 感染的脾脏的特点是骨髓细胞浸润增加，以及骨髓细胞和淋巴细胞增殖增加。细胞增殖增加与脾脏中示踪剂摄取增加相关。我们的研究结果支持使用 [ ¹⁸F]FDG 作为一种成像生物标志物，用于实时检测和跟踪 ZIKV 疾病，并突出受影响组织对病毒感染性质的依赖性。

结论

脾脏中的[ ¹⁸ F]FDG 摄取是一种有用的替代指标，可用于询问此 ZIKV 小鼠模型中的原位组织病毒负荷和炎症状态。