Serum Proteome and Cytokine Analysis in a Longitudinal Cohort of Adults with Primary Dengue Infection Reveals Predictive Markers of DHF

Autor: Steven R. Tannenbaum, Zheng Bo, Eng Eong Ooi, Cui Liang, Yadunanda Kumar, Jagath C. Rajapakse
Přispěvatelé: Massachusetts Institute of Technology. Department of Biological Engineering, Kumar, Yadunanda, Tannenbaum, Steven Robert, School of Computer Engineering
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: PLoS Neglected Tropical Diseases
PLos
PLoS Neglected Tropical Diseases, Vol 6, Iss 11, p e1887 (2012)
ISSN: 1935-2735
1935-2727
Popis: Background Infections caused by dengue virus are a major cause of morbidity and mortality in tropical and subtropical regions of the world. Factors that control transition from mild forms of disease such as dengue fever (DF) to more life-threatening forms such as dengue hemorrhagic fever (DHF) are poorly understood. Consequently, there are no reliable methods currently available for early triage of DHF patients resulting in significant over-hospitalization. Methodology/Principal Findings We have systematically examined the proteome, cytokines and inflammatory markers in sera from 62 adult dengue patients (44 DF; 18 DHF) with primary DENV infection, at three different times of infection representing the early febrile, defervescence and convalescent stages. Using fluorescent bioplex assays, we measured 27 cytokines in these serum samples. Additionally, we used multiple mass spectrometry methods for iTRAQ-based comparative analysis of serum proteome as well as measurements of protein adducts- 3-nitrotyrosine and 3-chlorotyrosine as surrogate measures of free radical activity. Using multiple methods such as OPLS, MRMR and MSVM-RFE for multivariate feature selection and classification, we report molecular markers that allow prediction of primary DHF with sensitivity and specificity of >80%. Conclusions/Significance This report constitutes a comprehensive analysis of molecular signatures of dengue disease progression and will help unravel mechanisms of dengue disease progression. Our analysis resulted in the identification of markers that may be useful for early prediction of DHF during the febrile phase. The combination of highly sensitive analytical methods and novel statistical approaches described here forms a robust platform for biomarker discovery.
Author Summary While the majority of patients who exhibit febrile dengue infection recover within a week, a small proportion of the patients progress to develop severe symptoms that can be life-threatening if not managed in a hospital setting. Because there is no method to accurately identify this subgroup of patients, many dengue patients are hospitalized unnecessarily, which causes significant burden to the healthcare system. In our study, we have systematically measured a large number of molecules including cytokines and serum proteins in blood samples from a dengue patient cohort using highly sensitive mass spectrometry-based methods. We have further developed novel statistical methods that allow us to identify small panels of measureable blood markers, which can distinguish dengue patients that develop milder, self-limiting form of the disease from those that progress to develop severe symptoms. Because these markers can be applied within 48–72 hours of onset of febrile symptoms, we expect them to be useful for early classification of severe dengue disease.
Databáze: OpenAIRE
Externí odkaz: