L2: Bacterial pathogens & disease- ENDOTOXINS Flashcards
What are LPS detected by?
→ TLRs
→ innate immune response
What are LPS?
→ major outer surface membrane components present in almost all Gram-negative bacteria
Name the components of gram negative bacterial cell wall
→ lipopolysaccharide → outer membrane → lipoprotein → peptidoglycan → cell membrane
Describe the structure of LPS
→ LIPID A
→ POLYSACCHARIDE CORE
→ O – SIDE CHAIN
What is lipid A in LPS?
→ Phosphorylated glucosamines attached to long chain fatty acids.
→ Number and type of fatty acid vary by species.
→ Hydrophobic
Describe the polysaccharide core of LPS
→Ketodeoxyoctanoic acid (KDO) and heptose.
→ Relatively constant between species
→ Hydrophilic
Describe the O-side chain of LPS
→ Repeat units of tri, tetra or penta-saccharide sugars.
→ Highly variable between species
→ Hydrophilic
What is the active component of LPS?
→ Lipid A
→ not immunogenic
What is the immunogenic component of LPS?
→ O-antigen
What is the major initiator of sepsis pathway?
→ LPS
Describe endotoxins
→ Heat stable
→ Not converted to toxoids.
→ Major initiator of the sepsis pathway
How are LPS molecules cross bridged and what does this allow?
→ non covalently cross bridged by Ca and Magnesium ions
→ barrier to hydrophobic molecules including bile salts
What is sepsis?
→ Life threatening organ dysfunction caused by a dysregulated host response to infection
What are the immune cells involved in sepsis?
→ macrophages, → monocytes, → granulocytes, → natural killer cells → dendritic cells
What do innate immune cells detect?
→ pathogen associated molecular patterns (PAMP’s) such as endotoxin,
→ damage associated molecular patterns (DAMP’s) from damaged host cells
How are DAMPs and PAMPs detected?
→ cell membrane receptors – toll-like receptors (TLR) and C-type lectin receptors
→ cytosol receptors - NOD-like receptors, RIG-I-like receptors
What are the two types of detectors of DAMPs and PAMPs?
→ cell membrane receptors
→ cytosol receptors
What are the effects of detection of PAMPs and DAMPs?
→ 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
After translocation to the nucleus, what is transcribed?
→ transcription of NF-kB
What are the 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
What are the effects of pro-inflammatory cytokines on neutrophils?
→ release extra-cellular traps (NETs)
→ release granules with antimicrobial activity
→ Cause release of microparticles by activated platelets
→ Increase tissue factor expression by blood monocytes
What are the functions of NETS?
→ proteins eg. histones that form a scaffold for platelet activation
What do microbes trapped in NETS do?
→ attracts and activate further leucocytes
What is produced in sepsis?
→ reactive oxygen species (ROS)
→ Hydroxyl and nitric oxide
→ Complements- 5a especially
What causes cells to hibernate in sepsis?
→ Mitochondrial damage
→ decreased intracellular ATP
What does widespread immunothrombosis lead to?
→ disseminated intravascular coagulation (DIC)
What does activation of complements lead to?
→ granulocyte enzyme release,
→ endothelial permeability
→ tissue factor expression
How is sepsis resolved?
→ Anti-inflammatory
IL-10 produced early in process
→ Autophagy of PAMP’s and DAMP’s
→ damaged cells undergo apoptosis
What do anti-inflammatories do in sepsis?
→ Supresses production IL-6 and γ-interferon
→ Stimulates production of soluble TNF receptor and IL-1 receptor antagonist
What is Meningococcal Sepsis caused by?
→ Neisseria meningitidis
→ Gram negative diplococcus
What are the serotypes of Meningococcal sepsis?
→ A,B,C, Y, W135
What is the difference in serotype A and B of meningococcal sepsis?
→ Serotype A associated with large outbreaks in Sahel region of Africa – Meningitis belt
→ Serotype B,C and W135 found in UK
What makes meningococcus so effective?
→ very active LPS
→ released from blebs
→lacks o-antigen
What are the symptoms of MS?
→ oedema
→ fever
→ dark purple rash
→ organ failure
