Dengue virusHuan-Yao Lei, Ph.D.

Department of Microbiology & Immunology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan

Dengue virus infection:Dengue epidemiologyDisease control and surveillancePathogenesis (Immunopathogenesis) Antibody-dependent enhancementDevelopment and challenge of Dengue vaccineDevelopment of anti-dengue virus drug?

Several important features of dengue diseaseDengue virus infection causes diverse disease spectrum from mild DF to severe DHF/DSS. Dengue disease can occur in infant, children, and adult.Severe DHF/DSS is more prevalent in secondary infection with different serotype of dengue virus. Antibody-dependent enhancement is hypothesized to explain the severe DHF/DSS in secondary infection.Thrombocytopenia and plasma leakage are two major characteristics of DHF/DSS.The pathogenesis of DHF/DSS is not clearly demonstrated. The progression from DF to DHF/DSS is not predictable.Supportive care is the only way to treat the DHF/DSS patients.Dengue vaccine is not commercially available yet.

Immune immature Primary infectionMaternal antibody effect ADE hypothesisSecondary infections with different serotypesHigher case fatality rate in elder in TaiwanComparative studyThe pathogenesis for DHF/DSS has to account for all these three entities in dengue virus infection.Infant (5%)Children (85%)Adult (10%)

Fig. 1 Rates in dengue modelby Shepard et al. Vaccine. 2004, 22:1275-1280.

Unique features of dengue disease in TaiwanDengue outbreak starts by imported case from abroad, spread out locally, then distinguish in the winter. This transmission pattern repeats every year. Put all efforts to eliminate breeding sources and control of infectant mosquitoes.Dengue disease primarily occur in adult.Dengue virus-infected elders with underlined diseases have high case fatality of DHF.Most clinicians are not familiar with the pathogenesis of dengue disease, and sometime have over or inappropriate medical treatment. The progression from DF to DHF/DSS is not predictable.Dengue vaccine is not commercially available or considered yet.

Halstead SB et al. Am J Trop Med Hyg 1969, 18:997-1021.Age-specific DHF/DSS hospitalization in children and infant.

DFDHF/DSS FatalAge-specific prevalent rate of DF, DHF/DSS and fatal cases in 2002 Kaohsiung outbreak.

The role of antibodies on dengue diseaseAb-dependent enhancementOld dogma for dengue virus-induced DHF/DSSAnti-prM Ab by its dual-specific binding of dengue virus and target cells to enhance the dengue virus infection.Enhancing antibodies are concentration-dependent and serotype-independent..Affected the design of dengue virus vaccine development..Pathogenic autoantibodyAcute dengue virus infection induces autoantibody productionAnti-dengue Abs cross-react with platelet and endothelial cell, and cause a transient hemophagocytic-like syndrome. Will have great impact on safety of dengue vaccine

Antibody-dependent Enhancement in Dengue Virus Infection: An Old but Unresolved DogmaEnhance the dengue-infected cell mass.Enhance the dengue virus replication?Suppress the anti-viral activity via FcRII signaling?The characteristics of the enhancing antibody? The target cells: requirement of receptors other than FcR?The dengue virion: E or prM? Which epitope?

Anti-E antibody:1. Neutralization2. Sub-neutralization3. EnhancingAnti-prM antibody:1. Enhancing2. NeutralizationEMBO J 2003, 22:2604

Anti-E Ab/Anti-prM Ab on FcR-bearing cells via FcgR-dependent mannerAnti-prM Ab on non-FcR-bearing cells via dual specific bindingADE of dengue virus infectionEnhancing antibodies for ADE are concentration-dependent, and serotype-independent.

Dengue infection: ImmunopathogenesisImmune deviationCytokine over-productionDengue virus-induced vasculopathyDengue virus-induced coagulopathyAnti-platelet autoantibody Anti-endothelial cell autoantibodyMolecular mimicryDengue virus infects monocytes and B cells

TCRabCD4CD8Representative CD4-TCRab, CD8-TCRab plots in two dengue patients.TCRab

Kinetic changes of CD4+ ( ), CD8+ T ( )lymphocytes, CD4/CD8 ratio ( ), CD4dim or CD8dim monocytosis ( )in dengue patient 2.F day0102030405060708000.51.01.52.0patient 2percentage (%)6912151821>250-3036912>250CD4/CD8 ratio, D day

Table 1. Summary of in 10 of 29 cases with CD4/CD8 ratio inversion.

Transient high elavation of IFN-g in DHF childrenDayIFN-g (pg/ml) 3 4 5 6 7 8 9 Control ( n = 1 7 12 15 2 2 14 4 )

Transient high elevation of IL-10 in DHF childrenDayIL-10 (pg/ml) 3 4 5 6 7 8 9 Control ( n = 1 7 12 15 2 2 14 4 )

Th1/Th2 Cytokine profile in DHF patients Infants (primary) Children (secondary)* IFN- (high) (high)

* TNF- (mild) No* IL-10 (high) (high) * IL-6 (moderate) No* IL-4, IL-2 No No

Issues need to be addressed in the next class:Why dengue is not controllable worldwide?Any measure for Taiwans dengue control and surveillance?Pathogenesis or immunopathogenesis? The mechanism of antibody-dependent enhancement?Dengue virus infection and autoimmunity?The prospect of Dengue vaccine development?The need for anti-dengue virus or disease treatment?

Thank Youfor Your Attention

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