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

2. 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. 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. Nature 408, 659-660 (7 December 2000) | Physiological Impact of Activation of Toll-like receptors include Tissue injury and sepsis

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. 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. Model Systems: C-type lectins and innate immunity 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. 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 Nature Med. 14 p648-55 The Ashwell receptor mitigates the lethal coagulopathy of sepsis

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