title: Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities.
abstract: BACKGROUND
  Dengue virus (DENV) is transmitted by the mosquito vector, and causes a wide range of symptoms that lead to dengue fever (DF) or life-threatening dengue hemorrhagic fever (DHF). The host and viral correlates that contribute to DF and DHF are complex and poorly understood, but appear to be linked to inflammation and impaired coagulation. Full-length osteopontin (FL-OPN), a glycoprotein, and its activated thrombin-cleaved product, trOPN, integrate multiple immunological signals through the induction of pro-inflammatory cytokines.
  
  
  METHODS
  To understand the role of OPN in DENV-infection, we assessed circulating levels of FL-OPN, trOPN, and several coagulation markers (D-dimer, thrombin-antithrombin complex [TAT], thrombomodulin [TM], and ferritin in blood obtained from 65 DENV infected patients in the critical and recovery phases of DF and DHF during a dengue virus epidemic in the Philippines in 2010.
  
  
  RESULTS
  Levels of FL-OPN, trOPN, D-dimer, TAT, and TM were significantly elevated in the critical phase in both the DF and DHF groups, as compared with healthy controls. During the recovery phase, FL-OPN levels declined while trOPN levels increased dramatically in both the DF and DHF groups. FL-OPN levels were directly correlated with D-dimer and ferritin levels, while the generation of trOPN was associated with TAT levels, platelet counts, and viral RNA load.
  
  
  CONCLUSIONS
  Our study demonstrated the marked elevation of plasma levels of FL-OPN and thrombin-cleaved OPN product, trOPN, in DENV-infection for the first time. Further studies on the biological functions of these matricellular proteins in DENV-infection would clarify its pathogenesis.
authors.affiliation: Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine; Laboratory of Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.
authors.forename: Haorile
authors.initials: H
authors.lastname: Chagan-Yasutan
authors.affiliation: Department of Blood Borne Diseases, San Lazaro Hospital, Manila, Philippines.
authors.forename: Talitha Lea
authors.initials: TL
authors.lastname: Lacuesta
authors.affiliation: Department of Tropical Medicine, John A. Burns School of Medicine, University of HI, Manoa, USA.
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.affiliation: Medical Informatics Division, Takeda General Hospital, Kyoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oguma
authors.affiliation: National Reference Laboratory for HIV/AIDS, Hepatitis, and other STDs, STD/AIDS Cooperative Central Laboratory, Manila, Philippines.
authors.forename: Prisca Susan A
authors.initials: PS
authors.lastname: Leano
authors.affiliation: National Reference Laboratory for HIV/AIDS, Hepatitis, and other STDs, STD/AIDS Cooperative Central Laboratory, Manila, Philippines.
authors.forename: Elizabeth Freda O
authors.initials: EF
authors.lastname: Telan
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Morita
authors.affiliation: Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.affiliation: Department of Blood Borne Diseases, San Lazaro Hospital, Manila, Philippines.
authors.forename: Efren M
authors.initials: EM
authors.lastname: Dimaano
authors.affiliation: Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine; Laboratory of Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan. Electronic address: hatoriaoi@gmail.com.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hattori
mesh_terms: D000990:Antithrombin III / Q000032:analysis / Q000276:immunology; D001777:Blood Coagulation; D003715:Dengue / Q000097:blood / Q000150:complications* / Q000276:immunology*; D003716:Dengue Virus / Q000502:physiology*; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000276:immunology / Q000821:virology; D053495:Osteopontin / Q000097:blood / Q000276:immunology*; D010447:Peptide Hydrolases / Q000032:analysis / Q000276:immunology; D013917:Thrombin / Q000032:analysis / Q000276:immunology*; D018180:Thrombomodulin / Q000032:analysis / Q000276:immunology
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D018180:Thrombomodulin; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D053495:Osteopontin; D000990:Antithrombin III; D010447:Peptide Hydrolases; D013917:Thrombin
keywords: Coagulation; Dengue virus; Full-length osteopontin; Inflammation; Thrombin; Thrombin-cleaved osteopontin