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1. Introduction
2. Innate immune sensing and response
3. How do we know when we have an infection?
4. The Pfeiffer phenomenon
5. LPS is an activator of innate immune response
6. Biological phenomenon
7. The C3H/HeJ mouse and the Lps locus
8. C3H/HeJ mice have a missense mutation of Tlr4
9. The "Dorsal group" in drosophila (1)
10. The "Dorsal group" in drosophila (2)
11. Chronology
12. TLR family
13. Signaling by the TLR family (1)
14. Signaling by the TLR family (2)
15. Forward genetics with ENU
16. Snowflake
17. Velvet
18. Piglet
19. Eel
20. Business class
21. Mask
22. Results to date
23. Positional cloning no longer requires fine mapping
24. Positional cloning scheme
25. A search for TLR signaling defects
26. This has led to these identifications
27. MyD88 independent signaling pathway
28. Mutations in the TLR signaling pathway
29. Spin phenotype (1)
30. Spin phenotype (2)
31. Spin macrophages produce normal amount of TNF
32. A Myd88 mutation fully suppress spin phenotype
33. Spin homozygotes develop autoimmunity
34. Germfree environment suppress autoimmunity
35. Spin is a missense allele of Ptpn6
36. Finding the role of SHP1 phosphatase (1)
37. Finding the role of SHP1 phosphatase (1)
38. Sensing is necessary but not the whole story
39. MCMV dose: lethality relationship over time
40. How many genes make a life-or-death difference
41. MCMV resistance: pathways for survival
42. Grey mutant mice
43. Genes involved in MCMV resistance (1)
44. MCMV-induced cytokines peak timings
45. Viral titres of Mayday mutants infected with MCMV
46. MayDay is hypersensitive to LPS
47. MayDay respond normally to TLR agonists
48. MayDay mutation is mapped to chromosome 6
49. 2 candidate genes in the MayDay critical region
50. The transmembrane topology of SUR2 and Kir6.1
51. Absence of Kir6.1 transcripts in MayDay mutants
52. LPS-perturbed gene expression in MayDay mice
53. Cardiac ischemia in Kir6.1-KO mice
54. dSUR plays a protective role against FHV
55. Linking endotoxemia to vasoconstriction
56. What causes the lethal effect of LPS in MayDay?
57. Genes involved in MCMV resistance (2)
58. Additional mutations
59. Some points about innate immunity

Topics Covered

• Sensing infection is essential to the initiation of an immune response
• The innate immune system senses signature molecules made by microbes using a conserved set of germline-encoded receptors
• This receptor family (the Toll-like receptors) was first understood when a mutation that abolished lipopolysaccharide (LPS) sensing was positionally cloned in mice
• In Drosophila a homologous receptor is also used to detect infection, and still another receptor activates a pathway evocative of the tumor necrosis factor (TNF) pathway in mammals
• Further work in mammals has depended upon gene targeting and also forward genetic work, which has revealed many of the components of the TLR signaling apparatus
• Forward genetics has also allowed us to see how many genes (and what kinds of genes) are important for resisting an infection in vivo

Links

Series:

• Innate Immunity

Categories:

• Immunology

Therapeutic Areas:

• Immunology & Inflammation

Talk Citation

Publication History

• Published on May 31, 2009

Financial Disclosures

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