title: Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes.
abstract: BACKGROUND
  Epidemic dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) are overwhelming public health capacity for diagnosis and clinical care of dengue patients throughout the tropical and subtropical world. The ability to predict severe dengue disease outcomes (DHF/DSS) using acute phase clinical specimens would be of enormous value to physicians and health care workers for appropriate triaging of patients for clinical management. Advances in the field of metabolomics and analytic software provide new opportunities to identify host small molecule biomarkers (SMBs) in acute phase clinical specimens that differentiate dengue disease outcomes.
  
  
  RESULTS
  Exploratory metabolomic studies were conducted to characterize the serum metabolome of patients who experienced different dengue disease outcomes. Serum samples from dengue patients from Nicaragua and Mexico were retrospectively obtained, and hydrophilic interaction liquid chromatography (HILIC)-mass spectrometry (MS) identified small molecule metabolites that were associated with and statistically differentiated DHF/DSS, DF, and non-dengue (ND) diagnosis groups. In the Nicaraguan samples, 191 metabolites differentiated DF from ND outcomes and 83 differentiated DHF/DSS and DF outcomes. In the Mexican samples, 306 metabolites differentiated DF from ND and 37 differentiated DHF/DSS and DF outcomes. The structural identities of 13 metabolites were confirmed using tandem mass spectrometry (MS/MS). Metabolomic analysis of serum samples from patients diagnosed as DF who progressed to DHF/DSS identified 65 metabolites that predicted dengue disease outcomes. Differential perturbation of the serum metabolome was demonstrated following infection with different DENV serotypes and following primary and secondary DENV infections.
  
  
  CONCLUSIONS
  These results provide proof-of-concept that a metabolomics approach can be used to identify metabolites or SMBs in serum specimens that are associated with distinct DENV infections and disease outcomes. The differentiating metabolites also provide insights into metabolic pathways and pathogenic and immunologic mechanisms associated with dengue disease severity.
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Voge
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Rushika
authors.initials: R
authors.lastname: Perera
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Sebabrata
authors.initials: S
authors.lastname: Mahapatra
authors.affiliation: Sustainable Sciences Institute, Managua, Nicaragua.
authors.forename: Lionel
authors.initials: L
authors.lastname: Gresh
authors.affiliation: Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministry of Health, Managua, Nicaragua.
authors.forename: Angel
authors.initials: A
authors.lastname: Balmaseda
authors.affiliation: Laboratorio de Arbovirología, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán, Mérida, Yucatán, México.
authors.forename: María A
authors.initials: MA
authors.lastname: Loroño-Pino
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Amber S
authors.initials: AS
authors.lastname: Hopf-Jannasch
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Belisle
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Blair
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Beaty
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood* / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000097:blood* / Q000821:virology; D003716:Dengue Virus / Q000502:physiology*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008800:Mexico; D008875:Middle Aged; D009527:Nicaragua; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011506:Proteins