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Case Study 3 Pathology and Mechanism of Dengue
Virus Infections
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Viral Infection Stage

• XTractor facts
• Cells infected Myeloid dendritic cells
• Dengue virus infection promotes translocation of
  High Mobility Group Box 1 protein from the
  nucleus to the cytosol in dendritic cells,
  upregulates cytokine production and modulates
  viral replication.
• Additionally, the TLR7-mediated recognition of DV
  RNA may be involved in pDC functional activation.

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Viral Infection Stage

• XTractor facts
• Molecules and processes involved
• Vimentin and microtubules
• In contrast, disruption of vimentin inhibited DV2
  infection
• VEGF and vascular leakage
• The experimental observation described here
  provided additional insights into potential
  mechanism for VEGF-mediated vascular leakage
  associated with DENV, and support the idea that
  there are potential applications of anti-VEGF
  therapeutic interventions for prevention of
  severe DENV infections
• In this study, the expression level of VEGF, a
  well-established vascular permeabilizing agent
  was shown to be elevated in a time-dependent
  manner, and exhibited a unique dual-response
  profile, in a DENV-infected endothelial cell.
• MMP2 and Vascular leakage
• Therefore, our results demonstrated that
  endothelial cells are an important target for DV
  infection, and that DV-induced MMP-2
  overproduction by direct infection of endothelial
  cells may contribute to the pathogenesis of
  severe dengue infection.
• CD209/ DC-SIGN
• There is evidence that infection of immature
  myeloid dendritic cells plays a crucial role in
  dengue pathogenesis and that the interaction of
  the viral envelope E glycoprotein with
  CD209/DC-SIGN is a key element for their
  productive infection.
• High levels of DV replication in mDC were found
  to correlate with DC-SIGN expression.

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Viral Replication Stage

• XTractor Facts
• Molecules and processes involved
• HMGB1
• Dengue virus infection promotes translocation of
  High Mobility Group Box 1 protein from the
  nucleus to the cytosol in dendritic cells,
  upregulates cytokine production and modulates
  viral replication.
• Chaperones Bip, Calnexin, Calreticulin
• Knocking-down expression of BiP, calnexin, or
  calreticulin by siRNA significantly decreased the
  production of infectious dengue virions.
• HSP60
• RNA interference mediated silencing of Hsp60 gene
  in human monocytic myeloma cell line U937
  revealed decreased dengue virus multiplication.
• polypyrimidine tract binding protein
• Nevertheless, whereas PTB knockdown led to a
  significant decrease in the accumulation of DENV
  viral RNAs, it did not impair translation.

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Pathology

• XTractor Facts
• Tryptophan Metabolism and IDO
• Gene expression analysis has shown up-regulation
  of genes involved in L-tryptophan catabolism in
  models of dengue virus (DENV)-infection in vitro.
  
• Our results demonstrate that IDO plays an
  important role in the antiviral effect of
  IFN-gamma against DENV infection in vitro and
  suggest a role in the immune response to DENV
  infections in vivo.
• Hemorrhage and iNOS
• Importantly, hemorrhage development and the
  severity of hemorrhage were greatly reduced in
  mice lacking iNOS or p47(phox) or treatment with
  oxidase inhibitor, pointing to the possibility of
  using anti-oxidant as therapeutics for dengue
  hemorrhage.
• Inflammation and Cytokines
• TNF and LTA Gene, Allele, and Extended HLA
  Haplotype Associations with Severe Dengue Virus
  Infection in Ethnic Thais.
• Severe dengue virus (DENV) infection is
  characterized by a cascade of cytokine
  production, including the production of tumor
  necrosis factor-alpha (TNF-alpha) and
  lymphotoxin-alpha (LT-alpha).
• HMGB1 regulated TNF-alpha, IL-6, IL-8 and
  IFN-alpha secretion in DENV infected DCs.

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Potential Targets for Treatment

• XTractor Facts
• iNOS/NCF1 or oxidases
• Importantly, hemorrhage development and the
  severity of hemorrhage were greatly reduced in
  mice lacking iNOS or p47(phox) or treatment with
  oxidase inhibitor, pointing to the possibility of
  using anti-oxidant as therapeutics for dengue
  hemorrhage.
• HSP60
• These observations suggest that, elevated levels
  of Hsp60 expression in virally infected cells may
  help in viral multiplication and could be
  possible therapeutic targets for the management
  of dengue virus infection.
• VEGF
• The experimental observation described here
  provided additional insights into potential
  mechanism for VEGF-mediated vascular leakage
  associated with DENV, and support the idea that
  there are potential applications of anti-VEGF
  therapeutic interventions for prevention of
  severe DENV infections.

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• Toxicity
• Clearance
• Dosing
• Target prioritization
• Off target effects
• Drug reusability studies
• Mutation/SNP analysis
• Pathway studies
• Disease mechanisms

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