Biological control of dengue

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Biological control of dengue

  1. 1. Biological Control of Dengue Dr. Ijaz Ali IBGE SAPCID
  2. 2. Introduction <ul><li>Dengue Virus </li></ul><ul><li>Dengue Vectors </li></ul><ul><li>Immunology of Dengue </li></ul><ul><li>Dengue Control Programs </li></ul><ul><li>Dengue Biological Control </li></ul><ul><li>Some Concerns </li></ul><ul><li>Active Research Areas </li></ul>
  3. 3. The Dengue Virus <ul><li>Dengue Fever: First reported in 1779. </li></ul><ul><li>Dengue Hemorrhagic Fever (DHF): 5% mortality. </li></ul><ul><li>Dengue Shock Syndrome (DSS): 40% mortality. </li></ul><ul><li>Flaviviridae; 70 members, Major cause of pathologies in human/animals. </li></ul><ul><li>Flavivirus (Human), Pestvirus (Animals), Hepacivirus. </li></ul><ul><li>Follow climatic events. </li></ul><ul><li>Arbovirus: Replicates both in vertebrates & invertebrates. </li></ul><ul><li>Category A pathogen. </li></ul><ul><li>10.5 kb Genome: 96 Whole Genome Sequences. </li></ul><ul><li>Four Serotypes: DEN1-4. 60-80% sequence homology. </li></ul><ul><li>Surface Protein Homology. </li></ul><ul><li>Problems with RNA Genomes: Frequent Mutations. </li></ul><ul><li>DEN2: The Asian American type causes DHF but the American type cause DHF in secondary infections. </li></ul>
  4. 4. The Virus <ul><li>Sri Lanka: Genetically distinct DEN3 with variable virulence. Strains isolated before 1989: No DHF. </li></ul><ul><li>DEN4 causes less sever disease. </li></ul>
  5. 5. Dengue Vectors <ul><li>The Aedes Mosquito </li></ul><ul><li>Aedes aegypti: Cosmopolitan. </li></ul><ul><li>Ae. Albopictus: South-East Asia. </li></ul><ul><li>Ae. Mediovittatus: Caribbean. </li></ul><ul><li>Ae. Polynesiensis: Western Pacific Region. </li></ul><ul><li>Distinct Physical Features </li></ul><ul><li>Habitats: Tropical/Sub-tropical. </li></ul><ul><li>Male feeds on plant nectar </li></ul><ul><li>Female needs a blood protein to synthesize </li></ul><ul><li>eggs. (Human, Animals, Birds, Monkeys). </li></ul><ul><li>Life Span: 14-21 days. </li></ul><ul><li>Lays 300 eggs during her life span </li></ul>Close-up of an Aedes mosquito
  6. 6. Transmission Cycles <ul><li>Forest </li></ul><ul><li>Forest species of Aedes </li></ul>Rural Peri-domestic Urban Domesticated Agypti + Albopictus <ul><li>Mosquito Feeding Habits </li></ul>
  7. 7. Worldwide distribution of Aedes aegypti , dengue virus serotypes, and dengue epidemic activity. Figure is modified from Gubler
  8. 8. Immunology and Pathogenesis of Dengue <ul><li>Pathogenesis: Two Theories [Immunological & Virological theories]. </li></ul><ul><li>Replication in a number of cells: </li></ul><ul><li>Macrophages, Monocytes , B cells, mast cells, Dendritic cells, Endothelial cells. </li></ul><ul><li>Viral entry: Fc-gamma receptors of the host cells. </li></ul><ul><li>Fc-gamma: Implicated in ADE. </li></ul><ul><li>The genetic determinants on E gene and the 5’ and 3’ untranslated regions (The viral Theory). </li></ul><ul><li>Dengue virus reactive T-cells: React differently with various serotypes. </li></ul><ul><li>Multiplicity of Genetic determinants. </li></ul>
  9. 9. Pathogenesis of Dengue <ul><li>Host genetic + Environmental + Viral factors </li></ul><ul><li>Absence of an animal model of disease: Candidate genes Identification for Susceptibility and Resistance. </li></ul><ul><li>Host Genetics: Variability at HLA I loci, Fc-gamma, Vit D receptor, promoter region of CD209 ---- Associated with distinct symptomatic phenotypes. </li></ul><ul><li>Host Immune pressure: Disease outcome + Viral evolution [within individual (quasispecies), or at geographic scale]. </li></ul><ul><li>Expression of special class I alleles: Associated with outcome. </li></ul>
  10. 10. The Non-ADE and ADE Pathway: Electron micrographs of Macrophages
  11. 11. Immunology of Dengue <ul><li>Antibody Dependant Enhancement [IgG not IgM]. </li></ul><ul><li>DEN1 (X Individual) ------ Ab (Anti-DEN1): [Life long Immunity] Ag:Ab complex (No entry into macrophages) </li></ul><ul><li>DEN 2/3/4 (X) ---- Activation of Immune system [Takes it for the primary infection] </li></ul><ul><li>Higher genetic similarity [ Similar surface proteins ]: The Immune system is tricked. Ab:Ag complexes [ No inactivation of the Ag ] </li></ul><ul><li>Macrophages are attracted and infected : Sever consequences, infection becomes more acute, body releases cytokines [makes endothelial tissue more permeable] ------ DHF and Fluid loss . </li></ul><ul><li>Vaccination & Passive acquisition of Abs in childern would have the same consequences. </li></ul>
  12. 12. Control Strategies <ul><li>Control of Immature stages: </li></ul><ul><li>Vector control [Larviciding with insecticides, elimination of breeding sites] </li></ul><ul><li>Only temephos, permethrin, Bti, and pyriproxyfen are approved by WHO for use in drinking-water. </li></ul><ul><li>Pyriproxyfen: Effective, new formulations are effective for 6 months, 1 ppb. Decrease fertility in adults. </li></ul><ul><li>Limitations: Prevents only eclosion, Larvae and Pupae are active. </li></ul><ul><li>BTi Toxins: Bacillus thuringiensis var. israelensis (Bti) </li></ul><ul><li>High larvicidal activity in mosquitoes. </li></ul><ul><li>Limitations: Combinations: BTi + Insecticide, BTi + Copepods: Effective but needs persistent follow up and supplementary food is needed. </li></ul><ul><li>Others: Insecticide treated materials, Lethal ovitraps at airports. </li></ul>
  13. 13. Control Strategies <ul><li>Biological Control Strategies: </li></ul><ul><li>Mosquito Densonucleosis viruses: Parvoviridae . </li></ul><ul><li>5 strains of Aedes DNVs. </li></ul><ul><li>Direct lethal effect or shorten the life span of the mosquitoes. </li></ul><ul><li>Limitation: Viral strains + Geographical location of vector = Variable outcome. </li></ul><ul><li>Predatory copepods: Mesocyclops spp. (Crustacea; Eudecapoda). </li></ul><ul><li>Control larvae. </li></ul><ul><li>Limitations: Effective in some regions but are lost when there is no water. </li></ul><ul><li>Monitoring and management is difficult. </li></ul>
  14. 14. Control Strategies <ul><li>Genetic Modification of the Mosquitoes: Using Wolbachia. </li></ul><ul><li>Stable Transformation of mosquitoes. </li></ul><ul><li>Raising mosquitoes in lab. </li></ul><ul><li>Collect the ova --------- microinjections of wolbachia into the germ line cells before cellularization. </li></ul><ul><li>Collect the surviving larvae and raise them in separate vials containing fly medium. </li></ul><ul><li>Cross the infected mosquitoes with wild type. </li></ul><ul><li>Test the progeny for the presence of wolbachia by PCR using wolbachia-specific primers. </li></ul><ul><li>Do more crosses to multiply the number. </li></ul><ul><li>Release into the wild. </li></ul>
  15. 15. Control Strategies <ul><li>Mechanism of the cross: Transformation of the Mosquito Population </li></ul><ul><li>Female Infected [ Wol+ ] X Male [Wild type] = Infected M/F. </li></ul><ul><li>Female [ Wild type ] X Male [ Infected Wol+ ] = Sterile Eggs. </li></ul>
  16. 16. Some Concerns <ul><li>Our focus: </li></ul><ul><li>Fumigations, Use of Insecticides, Strengthening Treatment and Diagnostics. </li></ul><ul><li>Limitations of the focused areas: </li></ul><ul><li>Economic concerns. </li></ul><ul><li>Environmental concerns. </li></ul><ul><li>Our social scenario and the existing operations. </li></ul><ul><li>Transportations. </li></ul><ul><li>Re-emergence? Cuba (1981-95). </li></ul>
  17. 17. Research Areas <ul><li>Transformation of the mosquito population. </li></ul><ul><li>Molecular Epidemiological Studies. </li></ul><ul><li>Association studies. </li></ul><ul><li>Comparative genomics and sequencing. </li></ul><ul><li>Immunology of the prevalent viral strains. </li></ul><ul><li>DHF/DSS: May well occur without pre-existing antibodies..? </li></ul><ul><li>New models of diseases. New targets? </li></ul><ul><li>Novel vector search. </li></ul><ul><li>Effective Predators. </li></ul>
  18. 18. <ul><li>Thanks </li></ul>

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