Presentation on theme: "Dengue virus Huan-Yao Lei, Ph.D."— Presentation transcript:
1Dengue virus Huan-Yao Lei, Ph.D. Department of Microbiology & Immunology,College of Medicine, National Cheng Kung UniversityTainan, Taiwan
2Dengue virus infection: Dengue epidemiologyDisease control and surveillancePathogenesis (Immunopathogenesis)Antibody-dependent enhancementDevelopment and challenge of Dengue vaccineDevelopment of anti-dengue virus drug?
3Several important features of dengue disease Dengue 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.
4Infant (5%) Children (85%) Adult (10%) Comparative study Immune immaturePrimary infectionMaternal antibody effectADE 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.
5Population Infection Clinical Cases DHF/DSS Asymptomatic DF (non-DHF) surviveDeath5%24%6%0.8%76%94%99.2%Fig. 1 Rates in dengue modelby Shepard et al. Vaccine. 2004, 22:
6Unique features of dengue disease in Taiwan Dengue 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.
7Age-specific DHF/DSS hospitalization in children and infant. Halstead SB et al. Am J Trop Med Hyg 1969, 18:
8DF DHF/DSS FatalAge-specific prevalent rate of DF, DHF/DSS and fatal cases in 2002 Kaohsiung outbreak.
9The role of antibodies on dengue disease Ab-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
10Antibody-dependent Enhancement in Dengue Virus Infection: An Old but Unresolved Dogma Enhance 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?
12ADE of dengue virus infection Anti-E Ab/Anti-prM Ab on FcR-bearing cells via FcgR-dependent mannerAnti-prM Ab on non-FcR-bearing cells via dual specific bindingEnhancing antibodies for ADE are concentration-dependent, and serotype-independent.
13Dengue infection: Immunopathogenesis Immune deviationCytokine over-productionDengue virus-induced vasculopathyDengue virus-induced coagulopathyAnti-platelet autoantibodyAnti-endothelial cell autoantibodyMolecular mimicryDengue virus infects monocytes and B cells
14Representative CD4-TCRab, CD8-TCRab plots in two dengue patients. DHF(patient 2)9 month afterwardDF(patient 5)CD4TCRabCD8TCRabRepresentative CD4-TCRab, CD8-TCRab plots in two dengue patients.
15Kinetic changes of CD4+ ( ), CD8+ T ( )lymphocytes, CD4/CD8 D day-336912>250802.0patient 270601.550CD4/CD8 ratio,401.0percentage (%)30200.5106912151821>250F dayKinetic changes of CD4+ ( ), CD8+ T ( )lymphocytes, CD4/CD8ratio ( ), CD4dim or CD8dim monocytosis ( )in dengue patient 2.
16Table 1. Summary of in 10 of 29 cases with CD4/CD8 ratio inversion.
17Transient high elavation of IFN-g in DHF children 20040060080010001200IFN-g (pg/ml)Day… Control( n = )
18Transient high elevation of IL-10 in DHF children 50100150200250IL-10 (pg/ml)… ControlDay( n = )
19Th1/Th2 Cytokine profile in DHF patients Infants (primary) Children (secondary)* IFN- (high) (high) * TNF- (mild) No* IL (high) (high) * IL (moderate) No* IL-4, IL-2 No No
21Issues need to be addressed in the next class: Why dengue is not controllable worldwide?Any measure for Taiwan’s 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?