2009 Demystifying Medicine:

1. 2009 Demystifying Medicine: Bacterial sepsis: A new epidemic and an old receptor

2. Bacterial sepsis: A new epidemic and an old receptor  • Innate Immunity gone awry: pathophysiology of Sepsis • Ashwell-Morell Receptor: C-type lectins and innate immunity • The Ashwell-Morell Receptor Mitigates the Lethal coagulopathy of sepsis • Reflections on the Discovery of the Asialoglycoprotein receptor: Gilbert Ashwell

3. What is the Innate Immune System?

4. Activation of Complement cascades

5. Interaction of Bacterial Surfaces with Toll-like receptors

6. Physiological Impact of Activation of Toll-like receptors include Tissue injury and sepsis Mammalian Toll-like receptors are expressed on a variety of immune cells, including monocytes and dendritic cells. Microbial lipoproteins activate mammalian immune cells through Toll-like receptor 2 (TLR2). Lipopolysaccharide activates these cells via TLR4. As shown by Hemmi et al.1, bacterial DNA sequences containing unmethylated cytosine–guanosine dinucleotides (CpGs) work through TLR9. The specificity of the other six mammalian Toll-like receptors is under investigation. Activation of Toll-like receptors kicks off signalling pathways that activate the transcription factor NF-B, resulting in transcription of genes that modulate and mediate immune responses. One result of these pathways is the release of pro-inflammatory cytokines, which have a say in the adaptive T-cell immune response. Another outcome (at least in fruitflies) is the activation of antimicrobial pathways that directly kill the pathogen. But the activation of Toll-like receptors can also be detrimental to the host. It can contribute to tissue injury in the form of apoptosis (programmed cell death) and the life-threatening symptoms of septic shock. During septic shock, infection leads to a failure of the circulatory system to supply sufficient nutrients and oxygen to tissues, and to remove metabolic wastes from those tissues. Nature408, 659-660 (7 December 2000) |

7. Sepsis: Impact on Coagulation Pathways

8. Mechanism of Sepsis

9. Summary: Events leading to Sepsis and Organ failure

10. Bacterial sepsis: A new epidemic and an old receptor • Innate Immunity gone awry: pathophysiology of Sepsis • Ashwell-Morell Receptor: C-type lectins and innate immunity • The Ashwell-Morell Receptor Mitigates the Lethal coagulopathy of sepsis • Reflections on the Discovery of the Asialoglycoprotein receptor: Gilbert Ashwell 

11. Pathways of Innate Immunity are Highly conserved

12. Model Systems: C-type lectins and innate immunity • 30 Drosophila C-type lectins-cellular encapsulation • 278 C-type lectins in C.elegans • Include vWF and CUB domains • Massive sequence variation • Pathogen-specific response during infection. Antimicrobial peptides Lysozyme Stress Detoxication +

13. Intracellular location and specificity of lectin classes

14. Bacterial sepsis: A new epidemic and an old receptor • Innate Immunity gone awry: pathophysiology of Sepsis • Ashwell-Morell Receptor: C-type lectins and innate immunity • The Ashwell-Morell Receptor Mitigates the Lethal coagulopathy of sepsis • Reflections on the Discovery of the Asialoglycoprotein receptor: Gilbert Ashwell 

15. Knockout of subunits of the Ashwell-Morell Receptor Impacts clearance of Asialo-glycoproteins Ashwell, Herz (1996) JBC 271:21160-6 Hanover, Sauer, Ashwell (1999) Gene 241:233-40 Nucleic Acids Res 27:e21 Yamada(2001) JBC 276:12624-8 2 ASGPR1 ASGPR2 ASGPR1 knockout

16. The Ashwell receptor mitigates the lethal coagulopathy of sepsis Nature Med. 14 p648-55 Endogenous ligands: Some ligands have 2-6 sialic acid Von Willebrand factor (vWF) Platelets ASGPR1 knockout mouse showed elevated vWF and increased susceptiblity to Streptococcus pneumoniae

17. Bacterial sepsis: A new epidemic and an old receptor • Innate Immunity gone awry: pathophysiology of Sepsis • Ashwell-Morell Receptor: C-type lectins and innate immunity • The Ashwell-Morell Receptor Mitigates the Lethal coagulopathy of sepsis • Reflections on the Discovery of the Asialoglycoprotein receptor: Gilbert Ashwell 

18. Ashwell-Morell Receptor Asialoglycoprotein receptor Hepatic lectin Gilbert Ashwell: Reflections on the Discovery of the Asialoglycoprotein Receptor