Serum Metabolome and Lipidome Changes in Adult Patients with Primary Dengue Infection

Background
Dengue virus (DENV) is the most widespread arbovirus with an estimated 100 million infections occurring every year. Endemic in the tropical and subtropical areas of the world, dengue fever/dengue hemorrhagic fever (DF/DHF) is emerging as a major public health concern. The complex array of concurrent host physiologic changes has hampered a complete understanding of underlying molecular mechanisms of dengue pathogenesis.
Methodology/Principle Findings
Systems level characterization of serum metabolome and lipidome of adult DF patients at early febrile, defervescence, and convalescent stages of DENV infection was performed using liquid chromatography- and gas chromatography-mass spectrometry. The tractability of following metabolite and lipid changes in a relatively large sample size (n = 44) across three prominent infection stages allowed the identification of critical physiologic changes that coincided with the different stages. Sixty differential metabolites were identified in our metabolomics analysis and the main metabolite classes were free fatty acids, acylcarnitines, phospholipids, and amino acids. Major perturbed metabolic pathways included fatty acid biosynthesis and β-oxidation, phospholipid catabolism, steroid hormone pathway, etc., suggesting the multifactorial nature of human host responses. Analysis of phospholipids and sphingolipids verified the temporal trends and revealed association with lymphocytes and platelets numbers. These metabolites were significantly perturbed during the early stages, and normalized to control levels at convalescent stage, suggesting their potential utility as prognostic markers.
Conclusions/Significance
DENV infection causes temporally distinct serum metabolome and lipidome changes, and many of the differential metabolites are involved in acute inflammatory responses. Our global analyses revealed early anti-inflammatory responses working in concert to modulate early pro-inflammatory processes, thus preventing the host from development of pathologies by excessive or prolonged inflammation. This study is the first example of how an omic- approach can divulge the extensive, concurrent, and dynamic host responses elicited by DENV and offers plausible physiological insights to why DF is self limiting.

研究背景：登革病毒（Dengue virus, DENV）是分布最为广泛的虫媒病毒，每年估计造成1亿人次感染。登革热/登革出血热（Dengue fever/Dengue hemorrhagic fever, DF/DHF）在全球热带与亚热带地区呈地方性流行，正日益成为重大公共卫生关切问题。宿主体内一系列复杂的并行生理变化，阻碍了学界对登革热发病机制背后分子机制的全面阐明。

研究方法与主要发现：本研究采用液相色谱-质谱联用法（liquid chromatography-mass spectrometry）与气相色谱-质谱联用法（gas chromatography-mass spectrometry），对成人登革热患者在登革病毒感染的早期发热期、退热期及恢复期的血清代谢组（serum metabolome）与脂质组（lipidome）开展系统层面的表征分析。本研究纳入44例样本（n=44），追踪三个典型感染阶段内的代谢物与脂质变化，由此成功识别出与不同感染阶段相契合的关键生理变化。代谢组学分析共鉴定出60种差异代谢物，主要代谢物类别涵盖游离脂肪酸、酰基肉碱、磷脂与氨基酸。受扰动的核心代谢通路包括脂肪酸生物合成与β-氧化、磷脂分解代谢、类固醇激素通路等，这表明人类宿主的应答具有多因素特性。针对磷脂与鞘磷脂（sphingolipids）的分析验证了其随时间变化的趋势，并揭示了其与淋巴细胞及血小板计数的关联。此类代谢物在感染早期阶段出现显著扰动，至恢复期时恢复至对照水平，提示其具备作为预后标志物的潜在应用价值。

结论与意义：登革病毒感染会引发血清代谢组与脂质组呈现时间特异性的动态变化，且多数差异代谢物参与急性炎症应答过程。本研究的全局组学分析揭示，早期抗炎应答与早期促炎过程协同发挥调控作用，从而避免宿主因过度或持续炎症而发展为病理损伤。本研究首次展示了组学方法如何揭示登革病毒引发的广泛、并行且动态的宿主应答，并为登革热具有自限性的生理学机制提供了合理的生物学阐释。