Bacterial Pathogens and Disease II- Endotoxins Flashcards
Describe Gram negative bacterial cell wall
- Peptidoglycan layer on top of cell membrane
- Lipopolysaccharides present on the outside of the cell wall
Describe the structure of a lipopolysaccharide
LIPID A:
- Phosphorylated glucosamines attached to long-chain fatty acids
- Number and type of fatty acid vary by species
- Hydrophobic
POLYSACCHARIDE CORE:
- Ketodeoxyoctanoic acid (KDO) and heptose
- Relatively constant between species
- Hydrophilic
O – SIDE CHAIN:
- Repeat units of tri, tetra or penta-saccharide sugars.
- Highly variable between species
- Hydrophilic
What are the characteristics of endotoxins
- Endotoxin is lipopolysaccharide (LPS)
- Lipid A is the active component. – not
immunogenic. - O antigen is highly immunogenic and immune
specific. - Found only in gram negative bacteria
- Heat stable
- Not converted to toxoids.
- Major initiator of the sepsis pathway.
What is sepsis
Life threatening organ dysfunction caused by a dysregulated host response to infection
What cells are involved in sepsis
- macrophages
- monocytes
- granulocytes
- natural killer cells
- dendritic cell
What do these cells detect
- pathogen associated
molecular patterns
(PAMP’s) such as
endotoxin, - damage associated
molecular patterns
(DAMP’s) from
damaged host cells.
What is this detection mediated by
- cell membrane
receptors – toll-like
receptors (TLR) and C
-type lectin receptors. - cytosol receptors -
NOD-like receptors,
RIG-I-like receptors
What is the effect of these cells
- Production of pro-inflammatory cytokines TNFα, IL-1, IL-6
- via inflammasomes to produce IL-1β and IL- 18 that cause rapid programmed cell death
What are the effects of pro-inflammatory cytokines
- Increase the number, lifespan and activation state of
innate immune cells - Increase adhesion molecule and chemokine
expression by endothelial cells - Increase acute phase protein such as complement,
fibrinogen and CRP - Cause fever.
- Causes neutrophils to release extra-cellular traps
(NETs) made of DNA and antimicrobial proteins that
forms a scaffold for platelet activation - Cause release of microparticles by activated
platelets - Increase tissue factor expression by blood monocytes
What is meant by the dysregulation of sepsis
The process described achieves rapid control of localised and minor infections
- However, the process may pass a threshold → systemic injury
Describe the 4 pathways of the dysregulation of sepsis
- Production of reactive oxygen species (ROS) - Hydroxyl and nitric oxide - damages cellular proteins, DNA and lipids and impairs mitochondria.
- Complement activation (esp. C5a) - increase ROS, granulocyte enzyme release, endothelial permeability and tissue factor expression.
- Widespread immunothrombosis leading to disseminated intravascular coagulation (DIC) with impaired microvasculature function and organ dysfunction.
- Mitochondrial damage leads to decreased intracellular ATP and cells enter state of hibernation - exacerbates organ dysfunction.
How is sepsis resolved
Active process - not passive
Anti-inflammatory
IL-10 produced early in process:
- Supresses production
IL-6 and y-interferon - Stimulates production of soluble TNF receptor and IL-1 receptor antagonist
Autophagy of PAMP’s and DAMP’s - removal
Damaged cells - undergo apoptosis and engulfment by macrophages
What is meningococcal sepsis
- Caused by Neisseria meningitidis
- Gram negative diplococcus
- Serotypes A,B,C, Y, W135
- Serotype A associated with large outbreaks in Sahel region of Africa – Meningitis belt.
- Serotype B,C and W135 found in UK – declined since introduction of MenC and now MenB vaccine.
- Can cause disease ranging from meningitis to life threatening meningococcal sepsis.
What makes meningococcus so effective in sepsis?
- LOS is shorter and lacks the O-antigen
- causes belting of the bacteria
