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1. Introduction
2. Malaria: the facts in 2007
3. The pathology of malaria is driven by cytokines
4. Life cycle of the malarial parasite
5. Why do humans get fever during malaria?
6. The search for the "malaria toxin" (1)
7. The search for the "malaria toxin" (2)
8. Is it a component of the outer membrane?
9. Gram negative cell envelope - LPS
10. Is the malaria toxin just like LPS?
11. Glycosylphosphatidyl inositol anchor (GPI)
12. GPI anchors activate TLR2
13. Purified P.falciparum failed to induce cytokines
14. The major immune-stimulus in malaria is not GPI
15. What is hemozoin?
16. Pure hemozoin failed to induce cytokines
17. Hemozoin levels and disease severity
18. Hemozoin production
19. Purification of hemozoin with a magnetic column
20. Purified hemozoin
21. Hypothesis (1)
22. What is a Toll receptor?
23. Identification of Toll receptors (1)
24. "Toll"
25. Toll receptor and TIR domain
26. Identification of toll receptors (2)
27. Toll receptor role in innate immune response (1)
28. Toll receptor role in innate immune response (2)
29. Toll innate immune response in humans and flies
30. TLRs in humans, mice and flies
31. The purple sea urchin has 222 TLRs
32. Innate immune recognition system 1997
33. Innate immune recognition system 2007
34. Domains of TLR
35. Shizuo Akira (1)
36. Bacterial DNA is rich in non-methylated CpG
37. Shizuo Akira (2)
38. Hz activates IL1 production via TLR9/MyD88
39. Activity of hemozoin is destroyed by DNase
40. Thus, DNA is the cytokine inducing component
41. Is the DNA on hemozoin human or malarial?
42. PCR analysis shows that most DNA is malarial
43. Can malaria DNA actually stimulate cells?
44. The cell biology of TLR9 is complex
45. TLR9 translocates to the endosome
46. Does malaria DNA activate innate immunity?
47. Malaria DNA is stimulatory only with DOTAP (1)
48. Malaria DNA is stimulatory only with DOTAP (2)
49. The malaria genome contains 269 CpG repeats
50. Current hypothesis
51. But, most malaria DNA is AT-rich
52. Patients with malaria show IFN signature
53. Hemozoin/DNA activates IFN-beta production
54. Malaria genome contains the motif ATTTTTAC
55. AT-rich ODN mimic malarial DNA
56. AT-rich ODN activate IFN-beta production
57. AT-rich ODN activate IFN independently of TLRs
58. AT-rich ODN activation of IFN requires IRF1
59. Is the inflammasome involved in the recognition?
60. The inflammasome
61. AT-rich ODN activate IL-1beta production
62. Activation of IL-1beta is via caspase-1
63. Malarial DNA activates the inflammasome
64. Is the inflammasome involved in IFN Generation?
65. Activation of IFN requires Nalp3 but not ASC
66. Activation of IL-1beta requires caspase 1
67. Hemozoin DNA - from phagosome to cytosol
68. Leakage after phagocytosis of inert particles
69. Alzheimer's disease
70. Beta amyloid
71. A-beta induces IL-1beta production in microglia
72. Beta-amyloid causes lysosomal swelling (1)
73. Beta-amyloid causes lysosomal swelling (2)
74. Beta-amyloid causes lysosomal leakage
75. Conclusion
76. Hypothesis (2)
77. Summary
78. Thanks

Topics Covered

• Malaria causes systemic inflammation, morbidity and death
• Toxic mediators: GPI anchor, Hemozoin/DNA
• DNA motifs: CpG (TLR9) and AT-rich (unknown receptor)
• Mechanisms of malarial sepsis-like syndrome, cerebral malaria

Links

Series:

• Innate Immunity

Categories:

• Clinical Practice
• Immunology
• Microbiology

Therapeutic Areas:

• Immunology & Inflammation
• Infectious Diseases

Talk Citation

Publication History

• Published on June 30, 2009

Financial Disclosures

• Prof. Douglas Golenbock has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.