Structure - LPS Flashcards
Lipopolysaccharides
A constituent of gram-negative bacteria membrane, providing integrity.
What are the three poritons of LPS?
Lipid A
Core Oligosaccharide
O Antigen
What is the function of Lipid A?
Anchors LPS to the membrane
Acts as an Endotoxin
What is the structure of Lipid A?
Two glucosamine residues linked by beta 1-6 glycosidic bonds with variable acyl chains.
What is an example of Lipid A alteration?
Phosphorylation of glucosamine alters charge/solubility.
How does Lipid A act as an endotoxin?
TLR4 pathway being a macrophage/DC expressed receptor
What does Lipid A interaction with TLR4 result in?
Signalling cascades and TF activation like NF-kb resulting in cytokine stimulation of inflammation.
What is an example of acyl chain variability?
Long chain C18 or C20 fa increases hydrophobicity and decreases solubility thus more prone to aggregation.
Why do longer Acyl chains have lower affinity for TLR?
Less stability between Lipid A and TLR4
What is the function of the Core Oligosaccharide?
Structural integrity LPS and a recognition site.
What is the structure of the Core Oligosaccharide?
Anchors Lipid A by 3-deoxy-D-manno-octulosonic acid with three structural regions( inner and outer core and terminal reigon)
Structure of CO inner core?
Heptose residue, 2-3 Kdo residues and N-Acetylcglucosamine
Structure of CO outer core
Terminated by galactose, glucose or NAG, bound by the terminal region
What is the function of the O-antigen Polysaccharide?An
Antigenic component
Host immune defense
Virulence Factor
What is the structure of the O Antigen?
Several dozen sugar residues
How does the O-antigen assist host infilitration?
Prevent recognition and binding of LPS like TLR
Virulence Factor
Bacteria associated molecules required for bacteria to cause disease whilst infection eukaryotic host.
What makes LPS amphiphatic?
Hydrophobic Lipid A and hydrophilic O-antigen and CO
What determines LPS effects on membrane packing?
Length and saturation of the acyl chains.
What happens when Lipid A binds TLR4?
Dimerisation bringing it into contact with cytoplasmic domains of two TLR, inducing downstream signalling pathways.
Anaphylatic Shock
This is an acute allergic reaction with airway and circulatory problems.
What is the most diverse component of LPS?
O Antigen.
What is the primary function of the LPS?
Establishes a permeabilit barrier, protecting cell from entry of toxic molecules.
Pathogenicity
The property of causing disease.
What makes LPS a strong barrier?
Its amphiphatic nature, and its ability to pack densely together.
What type of FA are Lipd A acyl portions?
Saturated FA.
How is condensing of LPS complicated?
Repulsion of the negatively charged phosphate groups.
How do LPS counter the negative repulsion of the phosphate groups?
Divalent cations like Mg which intercalate between LPS, forming interactions that enhance packing and promote barrier function.
What makes LPS an endotoxin?
Its prevalence on surface of bacteria, thus host immune systems respond dramatically to it.
What is an example of Lipid A structural diversity in relation to stimulation of TLR4?
Hexacylated, biphosphorylated Lipid A produced by E.Coli and Salmonella are highly immunogenic, whilst others are less so.
Immunogenic
Substances that can produce an immune response.
What are the ways GNB increase Lipid A diversity?
Covalent modifciations leading to changes in FA length, number of phosphates and carbohydrate moieties.
How might bacteria evade host immune response, with respect to Lipid A?
Production of less immunogenic Lipid A.
How does Yersinia Pestis modulate Lipid A response to TLR4?
Modulates acylation of LA at mammalian body temp, producing less immunogenic Lipid A.
How does temperature regulate Yersinia Pestis acylation?
At 37 degrees, Lipid A is tetraacylated, with weaker stimulation, but at lower temperatures, its hexacylated with increased stimulation.
What is the PagL gene?
A modifcation gene encoding Lipid A 3-0-deacylase in the outer mmebrane, modulation lipid A signalling.
Kdo moieties
3-Deoxy-D-Manno-2-octulosonic acid, a key cell wall component.
