Bacterial Pathogens and Diseases II (Endotoxins) Flashcards
LIPID A. - describe composition
Phosphorylated glucosamines attached to long chain fatty acids. No. and type of fatty acid vary by species. Hydrophobic
POLYSACCHARIDE CORE
- describe composition
POLYSACCHARIDE CORE
Ketodeoxyoctanoic acid (KDO) and heptose.
Relatively constant between species.
Hydrophilic
O – SIDE CHAIN
- describe composition
O – SIDE CHAIN
Repeat units of tri, tetra or pentasaccharide sugars.
Highly variable between species
Hydrophilic
Endotoxin - Characteristics
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.
Sepsis – What is it?
Life threatening organ dysfunction caused by a dysregulated host response to infection.
Sepsis primarily driven by
Sepsis primarily driven by the innate immune system response.
macrophages, monocytes, granulocytes, natural killer cells dendritic cells.
Sepsis detected by
macrophages, monocytes, granulocytes, natural killer cells dendritic cells.
pathogen associated molecular patterns (PAMP’s) such as endotoxin,
damage associated molecular patterns (DAMP’s) from damaged host cells.
Sepsis detection mediated by
cell membrane receptors – toll-like receptors (TLR) and C-type lectin receptors.
cytosol receptors - NOD-like receptors, RIG-I-like receptors.
Sepsis detection effect
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
Effects of pro-inflammatory cytokines
Increase 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
= formation of a thrombus (immunothrombosis)– microbes trapped within this. → attracts and activate further leucocytes.
Sepsis – what leads to systemic injury
Process described achieves rapid control of localised and minor infections.
However the process may pass a threshold → systemic injury
Sepsis - describe dysregulation
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.
Sepsis - describe resolution
Active process – not passive.
Anti-inflammatory IL-10 produced early in process
=
- Supresses production IL-6 and γ-
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.
Meningococcal Sepsis - cause
Caused by Neisseria meningitidis
Meningococcal Sepsis - types and their areas
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.
