Ward Michael D, Brueggemann Ernst E, Kenny Tara, Reitstetter Raven E, Mahone Christopher R, Trevino Sylvia, Wetzel Kelly, Donnelly Ginger C, Retterer Cary, Norgren Robert B, Panchal Rekha G, Warren Travis K, Bavari Sina, Cazares Lisa H
1Molecular and Translational Sciences Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702 USA.
2Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702 USA.
Clin Proteomics. 2019 Feb 7;16:7. doi: 10.1186/s12014-019-9227-3. eCollection 2019.
In-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host's immunological and physiological responses. Ebola virus (EBOV) causes a highly lethal infection termed Ebola virus disease (EVD) in primates and humans. The Gram negative non-spore forming bacillus () causes melioidosis in primates and humans, characterized by severe pneumonia with high mortality. We sought to examine the host response to infection with these two bio-threat pathogens using established animal models to provide information on the feasibility of pre-symptomatic diagnosis, since the induction of host molecular signaling networks can occur before clinical presentation and pathogen detection.
Herein we report the quantitative proteomic analysis of plasma collected at various times of disease progression from 10 EBOV-infected and 5 -infected nonhuman primates (NHP). Our strategy employed high resolution LC-MS/MS and a peptide-tagging approach for relative protein quantitation. In each infection type, for all proteins with > 1.3 fold abundance change at any post-infection time point, a direct comparison was made with levels obtained from plasma collected daily from 5 naïve rhesus macaques, to determine the fold changes that were significant, and establish the natural variability of abundance for endogenous plasma proteins.
A total of 41 plasma proteins displayed significant alterations in abundance during EBOV infection, and 28 proteins had altered levels during infection, when compared to naïve NHPs. Many major acute phase proteins quantitated displayed similar fold-changes between the two infection types but exhibited different temporal dynamics. Proteins related to the clotting cascade, immune signaling and complement system exhibited significant differential abundance during infection with EBOV or , indicating a specificity of the response.
These results advance our understanding of the global plasma proteomic response to EBOV and infection in relevant primate models for human disease and provide insight into potential innate immune response differences between viral and bacterial infections.
深入研究血浆蛋白质组对多种病原体感染的反应，有助于开发新的诊断模式，同时深入了解包括宿主免疫和生理反应在内的相互依存的致病过程。埃博拉病毒（EBOV）在灵长类动物和人类中引起一种高度致命的感染，称为埃博拉病毒病（EVD）。革兰氏阴性无芽孢杆菌（ ）在灵长类动物和人类中引起类鼻疽，其特征为严重肺炎，死亡率高。我们试图使用已建立的动物模型研究宿主对这两种生物威胁病原体感染的反应，以提供有关症状前诊断可行性的信息，因为宿主分子信号网络的诱导可在临床表现和病原体检测之前发生。
在此，我们报告了从10只感染EBOV和5只感染 的非人灵长类动物（NHP）在疾病进展的不同时间收集的血浆的定量蛋白质组分析。我们的策略采用高分辨率LC-MS/MS和肽标记方法进行相对蛋白质定量。在每种感染类型中，对于在任何感染后时间点丰度变化>1.3倍的所有蛋白质，与从5只未感染的恒河猴每天收集的血浆中获得的水平进行直接比较，以确定显著的倍数变化，并确定内源性血浆蛋白丰度的自然变异性。
与未感染的NHP相比，共有41种血浆蛋白在EBOV感染期间丰度发生显著变化，28种蛋白在感染 期间水平发生变化。定量的许多主要急性期蛋白在两种感染类型之间显示出相似的倍数变化，但表现出不同的时间动态。与凝血级联、免疫信号和补体系统相关的蛋白在感染EBOV或 期间表现出显著的丰度差异，表明反应具有特异性。
这些结果推进了我们对人类疾病相关灵长类动物模型中EBOV和 感染的全球血浆蛋白质组反应的理解，并深入了解病毒和细菌感染之间潜在的先天免疫反应差异。
