Sensing Microorganisms - Innate System Flashcards
Challenges posed for the innate sensing system?
Rapidly detecting diverse range of pathogens and distinguish from self
Recognising individually specific pathogens (memory)
Remembering previous pathogen encounters
First 2 points can’t be done by same cells
Solution is interwoven innate and adaptive systems
Innate sensing properties?
-recognise generic danger signals
Common evolutionary conserved pathogen molecules (PAMPs)
Molecules produced by damaged cells (DAMPs)
-limited receptor diversity
- not adaptable- receptors germline coded
-cells of same and different innate lineages share same receptors and recognise same molecules
Adaptive sensing properties?
-can recognise almost any microbial or non mocrobial molecule (Ags)
-very large almost infinite receptor diversity due to adaptability - receptors created by somatic recombination of gene segments
-each cell has one unique receptor that is highly specific for particular molecule
What is complement system?
Collection of proteins working together as early warning system and to destroy pathogens
Recruitment of immune cells
Label microbes for phagocytosis
Lyses pathogens by ripping holes into them
How does complement detect microbes?
Activated in 3 ways:
Direct recognition:
-alternative pathway
-lectin pathway
Via adaptive immunity and antibodies:
-classical pathway
Alternative pathway?
- Complement protein C3b spontaneously produced through cleavage of C3
- C3b binds amino and hydroxyl groups on microbes (present on large amounts of pathogens but also host cells).
- Complement effector mechanisms activated
Host cells need a way to block C3b activity or it will attack host
Works but better to detect host microbe molecules 🐮
Lectin pathway?
Mannose binding lectin binds to mannose found on surface of many common pathogens (yeast bacteria virus)
Interacts with C3b somehow unclear in notes (just recruits it somehow?)🐮
Complement effector mechanisms activated
MBL doesn’t bind to carbohydrates on healthy mammal cells
PAMPs?
Pathogen associated molecular patterns
Innate system recognises evolutionary conserved molecules shared by various classes of microbes and are not present on normal host cells (eg mannose)
PRRs?
Pattern recognition receptors
Proteins/receptors of innate system that recognise PAMPs
Eg mannose binding lectin, TLR, RIG, NLR
immune cells have PRRs on their surface, allow them to detect danger
Types of phagocytes?
Neutrophil
Macrophage
Sentinel cells?
Macrophages, Dendritic cells
Use phagocytosis to sample environment for microbes
Talk to T cells and show them any microbial molecules they’ve detected (APCs, antigen presenting cells)
Activate T cells
Macrophage as a sentinel?
Don’t move from infection site
Talk to T cells at infection site
Good killer
Good all rounder
Found in all barrier tissues
In their resting state they:
-mop up apoptotic cells
-Remove debris
-sample the environment
-scan for danger via PRRs
Dendritic cells as sentinels?
Migrate from infection site to lymph node
Talk to T cells in LN and infection site
Don’t kill
Specialised in talking to T cells
Fist danger signal?
Tissue damage
PRRs on innate cells recognise molecules from damaged/necrotic cells (DAMPs)
Potential break in barrier
Microbes causing damage while invading
Causes yellow warning - does not necessarily mean infection:
Activation of complement pathway
IFN-gamma and TNF-alpha cytokines
Activates macrophages to make them better at phagocytosis for killing and sampling and cause them to express surface receptors for communication with adaptive immune cells (MHC receptors)
Second danger signal?
PAMPs
Can lead to red alert
Macrophages activated further
Increased size
Enhanced phagocytosis
Release toxic molecules
Better killer
Release cytokines
Advantage of PRRs being germline encoded?
Are immmediately ready to go - fast response
One innate cell can express multiple PRRs - respond to wide range of microbes
How can innate tell between classes of microbes
Different classes have different PAMPs
Gram negative bacteria - LPS in wall
Gram positive bacteria - Lipoteichoic acid in wall
Bacteria - unmethylated CpG DNA in base genetic material, flagellin in flagellum
Viruses- dsRNA
Fungi- cell wall glucans
PRR localisation?
Can be either intra- or extracellular
Pathogen methods of avoiding recognition?
Modification of their PAMPs:
Salmonella spp. can modify its LPS reducing its PRR activating ability
Inhibition of PRR signalling pathways:
Vaccinia virus, Ebola virus, hepatitis C virus, influenza A virus
Inflammation properties?
Caused by pro-inflammatory cytokines
Eg TNF-alpha
-recruit immune cells to infection site
-activate immune cells to yellow alert
-stimulate production of acute pause proteins eg CRP
-tissue redness, swelling, heat
-fever
Neutrophil properties?
Recruited from blood to infection site
Phagocytose pathogens
Release destructive chemicals
What cytokine can activate macrophages?
IFN-gamma
Macrophage interactions with PAMPs, DAMPs and cytokines?
Pamps and damps can directly activate macrophage
They also stimulate cytokine (eg IFN-gamma) release from eg Natural killer cells which can also activate macrophages
Activated macrophages release cytokine (eg TNF-alpha)
This innate immune activity then leads to initiation of adaptive response
Resolving inflammation?
Pathogens get killed 🐮
Without stimulation:
Neutrophils short lived and apoptose
Macrophages apoptose or revert back to rest state
NK cells apoptose or revert back to resting and continue body patrolling
Danger from cytokines if infection isn’t cleared?
Cytokines provide powerful feedback loop of activation
If infection becomes systemic and can’t be cleared then this feedback loop keeps causes sepsis
Sepsis causes low blood pressure
Which causes septic shock
Symptoms of sepsis?
Inhibits heart contractions
Fluid leaks into tissues
Increased blood clotting
Cachexia (muscle wasting)
These cause reduced blood pressure
Which then causes septic shock
What can cause increased sepsis susceptibility?
Polymorphisms in TLR4 (the PRR for LPS) associated with increased susceptibility
Innate sensing advantages?
PAMPs allow distinguishing microbe from self
PAMPs indicate to immune system the type of microbe
Recognition of essential conserved PAMPs makes evasion of detection difficult for pathogens
Small number of different PRRs - wide range of microbes detected
Receptors germline encoded don’t need modification- ready to go allows quick response to infection
Multiple different cell types can express many PRRs allowing all to respond to infection
One cell can express multiple different PRRs allowing it to respond to a range of pathogens
Innate sensing disadvantages?
Not v specific - only gives rough idea of microbe type
Not adaptable except via evolution
Didn’t allow development of immune memory
