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

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2009 Demystifying Medicine:

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





What is the Innate Immune System?

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Activation of Complement cascades





Interaction of Bacterial Surfaces with Toll-like receptors





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 includeTissue injury and sepsis



Sepsis: Impact on Coagulation Pathways



Mechanism of Sepsis



Summary: Events leading to Sepsis and Organ failure





Pathways of Innate Immunity are Highly conserved

• 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

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Antimicrobial peptidesLysozymeStressDetoxication

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Intracellular location and specificity of lectin classes

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20

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60

80

100

120

0 5 10 15 20 25

Clearance time (min)

% ASOR clearance

wildtype ASGR1 -/- ASGR2 -/-



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 241:233-40Nucleic Acids Res 27:e21

Yamada(2001) JBC 276:12624-8

2 ASGPR1ASGPR2

ASGPR1 knockout

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



Ashwell-Morell Receptor

Asialoglycoprotein receptor

Hepatic lectin

Gilbert Ashwell: Reflections on the Discovery of the Asialoglycoprotein Receptor

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

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