【目的】

人腺病毒（human adenovirus，HAdV）传染性较强，在密闭、拥挤环境中可能发生暴发。HAdV感染极为普遍，但目前国内并无疫苗或特异性治疗药物。因此，探索HAdV致病机制、寻找生物标志物对于寻找治疗靶点、促进患者病情控制、及早进行预后评价具有重要意义。本文将采用病例对照研究设计探索暴发疫情中HAdV显性感染者和隐性感染者的免疫特征，揭示HAdV显性感染者在急性期、恢复期以及隐性感染者的血清代谢谱，探索与HAdV感染相关的代谢通路和代谢生物标志物，并通过靶向代谢组学检测及细胞实验进行验证，为HAdV感染的早期诊断与临床治疗提供参考依据。

【方法】

本研究采用病例对照设计，HAdV显性感染者、隐性感染者和健康对照均招募自2018年2−3月HAdV-7暴发的军营。HAdV显性感染者根据临床诊断分为肺炎与上呼吸道感染（upper respiratory tract infection，URTI）两组。临床症状明显的患者收治于中国人民解放军总医院第五医学中心，收集人口统计学信息、临床表现和实验室检测数据。在患者入院和出院时分别采集血样，在疫情暴发初期采集隐性感染者和健康对照的血样。采用液相色谱联用质谱法进行代谢组学检测。进行单变量和多变量分析，根据变量投影重要性（variable importance projection，VIP）值、P值等指标筛选组间差异性代谢物，进行通路富集分析筛选差异代谢通路。绘制差异代谢物的受试者工作特征曲线（receiver operating characteristic，ROC），通过曲线下面积（area under curve，AUC）评价区分能力。使用ATCC的A549细胞系进行体外细胞实验，观察细胞接种HAdV和加入特定代谢物后的形态变化并测定病毒载量，验证HAdV感染的标志性代谢物。

【结果】

本研究共纳入67例HAdV-7感染者与14例健康对照，包括显性感染35例与隐性感染者32例。在显性感染组中，有肺炎患者14例与URTI患者21例。所有研究对象均为男性。HAdV感染者年龄中位数为21［四分位距（interquartile range，IQR）19，21］岁，BMI中位数为22.0（IQR 20.8，22.9）kg/m²，吸烟与饮酒的比例分别为51.8%与23.2%。HAdV感染者与健康对照的人口学信息组间差异均无统计学意义。与隐性感染者相比，显性感染者的年龄较小（19岁 vs. 21岁，P=0.002）。肺炎患者与URTI患者的人口学信息组间差异不具有统计学意义。

与健康对照相比，HAdV感染者的血小板计数更低；感染者中，显性感染者比隐性感染者的血小板计数更低。此外，与隐性感染者相比，显性感染者的中性粒细胞和单核细胞百分比更高，淋巴细胞百分比更低、计数更少，T细胞、B细胞、CD4⁺ T细胞、CD8⁺ T细胞和NK细胞计数更少。相比于隐性感染者，显性感染者的白介素-6（interleukin-6，IL-6）、IL-10、干扰素-α（human interferon-α，IFN-α）、IFN-β和干扰素γ诱导蛋白-10（interferon γ inducible protein-10，IP-10）水平较高，而高级糖基化终产物可溶性受体（soluble receptor for advanced glycation end products，sRAGE）水平较低。IL-6区分显性感染者与隐性感染者的效果最好，AUC达到0.9，其次为IP-10、IFN-β、sRAGE和IFN-α，AUC均≥0.8。从急性期至恢复期，HAdV感染者的IL-6、IFN-β和IP-10降低，sRAGE升高。肺炎患者的sRAGE水平低于URTI患者。

本研究筛选得到HAdV显性感染者与健康对照组间差异代谢物209种和差异代谢通路9条，HAdV隐性感染者与健康对照组间差异代谢物280种和差异代谢通路9条，两次比较均筛选得到次级与初级胆汁酸生物合成这两条差异代谢通路，且两条通路均包括牛磺胆酸和甘氨胆酸。靶向代谢组学与细胞实验结果验证了不同HAdV感染状态人群的胆汁酸水平差异和胆汁酸对病毒体外复制的抑制作用。本研究筛选得到HAdV显性感染者与隐性感染者差异代谢物612种和差异代谢通路5条。参与差异代谢通路的代谢物均具有较好的区分能力，其中9,10-环氧硬脂酸、四氢脱氧皮质酮、磷脂酰丝氨酸、视黄基酯的AUC=1。筛选得到急性期肺炎患者与URTI患者的差异代谢物57种、差异代谢通路9条，神经酰胺与乳糖神经酰胺为AUC最高的两个物质，且均为鞘脂代谢通路上的物质，神经酰胺与乳糖神经酰胺水平联合区分肺炎患者与URTI患者AUC为0.801。

【结论】

HAdV感染导致患者体内出现淋巴细胞组成失衡，以IL-6为主的免疫相关指标水平变化。HAdV感染状态与次级、初级胆汁酸生物合成紊乱相关，HAdV感染促进了胆汁酸与牛磺酸、甘氨酸的结合。胆汁酸的补充可能有利于干扰病毒感染和复制，为HAdV感染的临床治疗提供参考。甘油磷脂代谢与HAdV感染、炎症反应均存在相关，可能是HAdV感染后出现临床症状的关键通路。鞘脂代谢与HAdV感染从URTI进展为肺炎存在关联，差异代谢物包括神经酰胺和乳糖神经酰胺，这可能是潜在的肺炎生物标志物和治疗靶点，为HAdV感染的及早诊断与评估预后提供思路。

OBJECTIVE

Human adenovirus (HAdV) is highly contagious and may cause outbreaks in confined and crowded spaces. Its infection is extremely common, but there is no vaccine or specific therapeutic drug at present. Therefore, exploring the pathogenic mechanism of HAdV and searching for biomarkers have great significance in terms of finding therapeutic targets, facilitating disease control in patients, and conducting early prognostic evaluation. We used a case-control study to explore the immune characteristics of apparent and asymptomatic HAdV-infected patients in the outbreak, and to reveal the serum metabolic profiles of apparent HAdV-infected patients at the acute and recovery stages, as well as those of asymptomatic patients and healthy people, and to explore the metabolic pathways and metabolic biomarkers related to HAdV infection, which will be validated by targeted metabolomics and cellular experiments, in order to provide reference for the early diagnosis and clinical treatment of HAdV infection.

METHODS

A case-control design was used. Apparent and asymptomatic HAdV-infected patients and healthy controls were recruited from military camps with HAdV-7 outbreaks during February and March 2018. Apparent infected patients were categorized into patients with pneumonia and upper respiratory tract infection (URTI) according to clinical diagnosis. Patients with obvious clinical symptoms were admitted to the Fifth Medical Center of PLA General Hospital, where demographic information, clinical manifestations, and laboratory test data were collected. Blood samples were collected from patients at admission and discharge, and from asymptomatic patients and healthy controls at the beginning of the outbreak. Liquid chromatography (LC) coupled with mass spectrometry (MS) was used for metabolomics detection. Univariate and multivariate analyses were performed, and the differential metabolites were screened according to the variable importance projection (VIP) value, P value and other indexes. The differential metabolic pathways were screened for differences by pathway enrichment analysis. The receiver operating characteristic (ROC) curves of the differential metabolites were plotted, and the discrimination ability was evaluated by the area under curve (AUC). In vitro cellular experiments were performed using the ATCC A549 cell line and the cell morphology was observed and viral load was determined after being infected with HAdV and the addition of specific metabolites to validate the marker metabolites of HAdV infection.

RESULTS

A total of 67 HAdV-7-infected patients and 14 healthy controls were included in this study, including 35 cases of apparent infection and 32 cases of asymptomatic infection. Among the apparent infected patients, there were 14 patients with pneumonia and 21 patients with URTI. All study subjects were male. The median age of HAdV-infected patients was 21 (IQR 19, 21) years with the median of BMI being 22.0 (IQR 20.8, 22.9) kg/m², and the percentage of smoking and alcohol drinking were 51.8% and 23.2%, respectively. No statistically significant differences in demographic information were observed between HAdV-infected patients and healthy controls. Compared to those with asymptomatic infection, patients with apparent infection were younger (19 years vs. 21 years, P=0.002). No statistically significant differences in demographic information were observed between patients with pneumonia and those with URTI.

Platelet counts were lower in HAdV-infected individuals compared to healthy controls, and among infected individuals, those with apparent infection had lower platelet counts than those with asymptomatic infection. In addition, compared to asymptomatic patients, patients with apparent infection had higher percentages of neutrophils and monocytes, lower percentages and counts of lymphocytes, and lower counts of T cell, B cell, CD4⁺ T cell, CD8⁺ T cell, and NK cell. Compared to asymptomatic patients, patients with apparent infection had higher levels of interleukin-6 (IL-6), IL-10, human interferon-alpha (IFN-α), IFN-β, interferon γ inducible protein-10 (IP-10), high mobility group protein 1 (HMGB1) and lower levels of soluble receptor for advanced glycation end products (sRAGE). IL-6 had the best efficacy in differentiating patients with apparent or asymptomatic infection, with an AUC of 0.9, followed by IP-10, IFN-β, sRAGE, and IFN-α, all with an AUC of ≥0.8. From the acute stage to the recovery stage, IL-6, IFN-β, and IFN-α were increased and sRAGE was decreased in HAdV-infected patients. Patients with pneumonia had lower levels of sRAGE than patients with URTI.

A total of 209 differential metabolites and nine differential metabolic pathways were screened between patients with HAdV apparent infection and healthy controls, and 280 differential metabolites and nine differential metabolic pathways were screened between patients with HAdV asymptomatic infection and healthy controls. Two differential metabolic pathways, secondary and primary bile acid biosynthesis, were noted between the two analyses, and both pathways were hit by taurocholic acid and glycocholic acid. The results of targeted metabolomics and cellular experiments verified the differences in bile acid levels among groups and the inhibitory effects of bile acids on viral replication in vitro. A total of 612 differential metabolites and five differential metabolic pathways were screened between patients with apparently or asymptomatic infection. The metabolites involved in the differential metabolic pathways had good discrimination ability, among which 9,10−epoxyoctadecenoic acid, tetrahydrodeoxycorticosterone, phosphatidylserine, and retinyl ester had AUC = 1. A total of 57 differential metabolites and nine differential metabolic pathways were screened between patients with pneumonia or URTI at the acute stage. Ceramide and lactose ceramide were the two metabolites with the highest AUC, and both were in the sphingolipid metabolic pathway. Combining the levels of ceramide and lactose ceramide to differentiate between patients with pneumonia or URTI, the AUC obtained was 0.801.

CONCLUSION

HAdV infection led to an imbalance in the cellular composition of lymphocytes and changes in the levels of immune-related markers, mainly IL-6, in patients. The HAdV infection was associated with disturbances in the secondary and primary bile acid biosynthesis. HAdV infection promoted the binding of bile acids to taurine and glycine. Bile acid supplementation may be beneficial in interfering with viral infection and replication, providing reference for the clinical treatment of HAdV infection. Glycerophospholipid metabolism correlated with both HAdV infection and inflammatory response, and may be a key pathway for the development of clinical symptoms after HAdV infection. Sphingolipid metabolism was associated with the progression of HAdV infection from URTI to pneumonia, and the differential metabolites include ceramides and lactose ceramides, which may be potential pneumonia biomarkers and therapeutic targets, providing ideas for early diagnosis and assessment of prognosis of HAdV infection.

第一章 引言 1
1.1 研究背景 1
1.1.1 HAdV概述 1
1.1.2 HAdV感染的免疫特征研究进展 2
1.1.3 HAdV代谢组学研究进展 4
1.2 研究目的 6
1.3 研究内容 6
1.3.1 探索HAdV感染患者免疫特征 6
1.3.2 探索HAdV感染患者代谢特征 6
第二章 对象与方法 8
2.1 资料来源 8
2.2 研究对象 8
2.3 资料收集方法 8
2.3.1 信息收集与采样 8
2.3.2 HAdV检测与免疫指标检测 9
2.3.3 细胞实验 10
2.3.4 LC–MS分析 11
2.4 资料分析方法 12
2.5 质量控制 12
2.6 技术路线 13
第三章 结果 14
3.1 HAdV感染的免疫特征 14
3.1.1 一般情况 14
3.1.2 淋巴细胞亚群 17
3.1.3 免疫活性物质 19
3.2 HAdV感染的代谢特征 22
3.2.1 一般情况 22
3.2.2 HAdV感染者与健康对照 25
3.2.3 HAdV显性感染者与隐性感染者 38
3.2.4 HAdV感染肺炎患者与URTI患者 46
第四章 讨论 62
4.1 HAdV感染的免疫特征 62
4.2 HAdV感染的代谢特征 64
4.2.1 HAdV感染者与健康对照 64
4.2.2 HAdV显性感染者与隐性感染者 65
4.2.3 HAdV感染肺炎患者与URTI患者 66
4.3 研究局限性 67
第五章 结论与展望 68
参考文献 69
附录A 77
文献综述 79
致 谢 89
北京大学学位论文原创性声明和使用授权说明 91
个人简历、在学期间发表的学术论文与研究成果 93
答辩委员信息 95
答辩委员会决议书 97

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