Bacterial Pathogens and Disease 2 Flashcards
What is the structure of gram negative bacteria ?
Lipopolysaccharides are essential parts of the bacterial cell wall.
Gram negative have an inner and outer membrane with a layer of peptidoglycan in the middle-within the periplasm.
In the outer membrane near the porin and integral proteins there is a polysaccharide /endotoxin.
This is anchored by lipid A and contains a core and a protruding part called an o-polysaccharide .
What is a lipopolysaccharide (LPS)made up of ?Identify its components
The Lipid A component which is made up of phosphorylated glucosamine and long fatty chain -this is involved in the toxicity of the molecule/diverse in different species
Core of rare uncommon saccharides carbohydrates
this is stable and not very diverse /conserved
Protruding part which is in contact with the environment. This interacts with immune system antigenic. Highly variable even within strains of same species of bacteria.
This o- chain can be immunogenic and antibodies can be produced against it.
(This can protect the bacteria against the complement”
Outline the three main components of lipopolysaccharide
1.Lipid A
Phosphorylated glucosamines attached to long chain fatty acids
Number and type of fatty acid vary by species
Hydrophobic
2.Polysaccharide core Ketodeoxyoctanic acid (KDO) and heptose Relatively constant between species Hydrophilic
3.O-side chain
Repeat units of tri,tetra and Pentasaccharide sugars
Highly variable between species
Hydrophilic
What are the characteristics of endotoxins?
- Endotoxin is lipopolysaccharide (LPS)
- Lipid A is the active component -not immunogenic (substances able to produce an immune response.)
- O-antigen is highly immunogenic and immune specific
- Found only in gram negative bacteria
- Heat stable
- Not converted to toxoids
- Major initator of the sepsi pathway
Define Sepsis
Life threatening organ dysfunction caused by dysregulated host response to infection
How is Sepsis driven?
It is driven by the innate immune system : Macrophages Monocytes Granulocytes Natural killer cells Dendritic cells
+role of the detectors of pathogen patterns
What do the innate immune system cells detect ?
OPEN SLIDE
Detect pathogens through signals/receptors on cell surface
What are the effects of pro-inflammatory cytokines ?
They increase number /lifespan /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 NDA and antimicrobial proteins=forms a scaffold for platelet activation
Cause release of microparticles by activated platelets
Increase tissue factor expression -blood monocytes
During sepsis steps 5,6,7 are increased leading to blockages and coagulation
Thrombus (Immunothrombosis -microbes become trapped within this structure
How does sepsis lead to dysregulation ?
Process described achieves rapid control of localised and minor infections
Sepsis happens when specific gram-negative bacteria gain access to blood stream .
If normal innate immune activation is passed through threshold this can lead to systemic injury
What happens in sepsis cases ?
Gram-negative bacteria is in the blood ,hyperactivation with productin of ROS(reactive oxygen species) damages cellular proteins ,DNA ,lipids and impairs mitochondria
Complement activation (esp C5a)-increase ROS granulocyte enzyme release,endothelila permeability , tissue factor expressio
Widespread immunothrombosis =Intravascular coagulation with impaired microvasculature function and organ dysfunction
Mitochondrial damage leads to decreased intracellular ATP and cells enter state of hibernation -exacerbates organ dysfunction
Outline sepsis resolution
This is an active process
Anti-inflammatory IL-10 produced early during the process =Supresses production of IL-6 and gamma -interferon , stimulates production of soluble TNF receptor ands IL-1 receptor antagonist
Autophagy of PAMPS and DAMPS removal
Damaged cells-undergo apoptosis and engulfment by macrophages
Outline Meningococcal sepsis
This is caused by Neisseria meningitidis
Gram negative diplococcus
CHECK SLIDE
What makes Meningococcal sepsis effective at causing sepsis ?
The structure of the LPS :
Hexa-acylated Lipid A and terminal residue mimicry
-Can activate and dysregulate immune reponse
Blebs
-secreted capsules of the membrane
Small amount of inoculate can compound hyperactivity.
These blebs are heavily covered by LPS -induce sepsis
What are some clinical observations of sepsis?
Pressure applied to the skin , there is deformation ,depression of tissue -sign of oedema
Rash -small haemorrhages
Do not go away-Immuno thrombosis
consequences: vascular disseminated coagulation ,organ failure and can be fatal
