Abstract
Osteopontin (OPN) is a multifunctional matricellular protein produced by a broad range of cells including osteoclasts, macrophages, T cells, endothelial cells, and vascular smooth muscle cells. OPN modulates various physiological and pathological events such as inflammation, wound healing, and bone formation and remodeling. Dengue virus (DENV) infection causes an increase in plasma OPN levels, which is correlated with the severity of symptoms and coagulation abnormalities. DENV infection also induces OPN gene expression in human macrophages. This study investigated the inhibitory effects of brefelamide and its methyl ether derivative on DENV-3 by measuring changes in OPN levels in human THP-1 and 293T cell lines infected at different multiplicities of infection and post-infection time points. OPN mRNA expression and viral RNA were detected by reverse transcriptase quantitative real-time PCR, whereas protein level was determined by enzyme-linked immunosorbent assay. We found that viral copy number was higher in 293T than in THP-1 cells. However, THP-1 constitutively expressed higher levels of OPN mRNA and protein, which were enhanced by DENV-3 infection. Brefelamide and its derivative suppressed OPN production in DENV-3 infected THP-1 cells; the effective doses of these compounds had no effect on uninfected cells, indicating low cytotoxicity. These results suggest that brefelamide and its methyl ether derivative have therapeutic effects in preventing inflammation, coagulopathy, and fibrinolysis caused by OPN upregulation induced by DENV-3 infection.
Highlights
Dengue is mosquito-borne, acute, febrile disease prevalent in tropical and subtropical areas
Cells infected at multiplicity of infection (MOI) of 0.1 resulted 12.59-fold higher OPN levels after 3 days than those infected at MOI = 0.01 (P < 0.005)
These results indicate that dengue virus (DENV) infection induces OPN synthesis in THP-1 cells
Summary
Dengue is mosquito-borne, acute, febrile disease prevalent in tropical and subtropical areas. Osteopontin in DENV-3 Infected Cells fever and dengue shock syndrome (DHF/DSS). Dengue fever is a flu-like syndrome, but severe DHF is characterized by coagulopathy and increased vascular fragility and permeability. The highest risk is associated with DHF that progresses to DSS, whereby hypovolemic shock can lead to death (Abel et al, 2012). The molecular mechanisms underlying the progression of dengue illness are not fully understood, they are presumed to be associated with increased coagulation and fibrinolytic activity during DENV infection (Avila-Aguero et al, 2004; HuertaZepeda et al, 2008) resulting from elevated levels of thrombinantithrombin complex, D-dimer (fibrin degradation product), tissue plasminogen activator, and prothrombin fragment (Suharti et al, 2002; Wills et al, 2002)
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