16. Host Pattern Recognition and Avoidance Flashcards
Why could allergy and autoimmune conditions be increasing?
hypothesis: a lack of exposure to pathogenic and commensal bacteria caused by a more clean modern environment
what is transient exposure?
specific short term exposure experienced by people at different points in time
What is the most common type of exposure to pathogens?
transient
why is commensal flora essential for life?
they help the body sense bacteria and respond appropriately to both commensal and pathogenic bacteria
why is the absence of TLR stimulation detrimental to health?
causes dysregulation of signalling pathways causing a lack of response to tissue damage and lack of barrier integrity
What helps develop the signalling pathways?
the commensal microbiota stimulating signalling pathways
what is an immunological paradox?
the cells interacting with the microbiota need to decide what to tolerate and what to mount an immune response to
What is needed to maintain barrier function?
Stimulation of TLR and NLR by commensals helps maintain intestinal homeostasis
what is the normal immune response signalling pathway?
Recognition of PAMPs by PRR
signal transduction
induce changes in gene expression
(inflammation)
what is one of the most commonly studied TLR?
TLR-4 that recognises LPS
why is compartmentalisation of TLR receptors important?
So the receptors are in the right place to detect the pathogen motif and the response occurs in the correct place in the cell
where would TLRs that detect lipoproteins LPS and viral components be?
on the external surface of the cell
Where would TLRs that detect pathogenic RNA/DNA be?
on the endosome
What are the roles of TLRs and NLRs?
regulate NF-kB, MAPK, IRF pathways that cause proinflammatory and antimicrobial gene products
what effects do TLR have on immature dendritic cells?
Activate them
secrete cytokines
express costimulatory molecules
express MHC-2
Induction of migration to secondary lymphoid organs
What is the distribution of PRRs in mammals?
not all cells express all PRR
different TLR, NLR and RIH are expressed differently in different cell types and different cell compartments
what do all PRRs do?
signalling cascades that regulate gene expression to counteract infection
proinflammation
antimicrobial peptides
What should PAMPS really be called?
MAMPS - microbe-associated molecular patterns
can the microbiota trigger PRR?
yes they all have pathogenic components
why doesn’t the microbiota trigger an immune response?
to distinguish between commensal and pathogenic bacteria a secondary signal must be needed to trigger the response
What is the Janeway hypothesis?
that a second signal is needed to trigger a full immune response to ensure the response to proportional to the pathogen
what is the first signal needed for a full immune response?
PAMP - PRR interaction to prime the immune system
what is the second signal needed for a full immune response?
Patterns of pathogenesis
what are patterns of pathogenesis?
cell or tissue damage
molecules secreted by infected cells
detection of secreted toxins
when do you gain you gut microbiota?
As soon as amniotic sack bursts you start to be colonised
what are the first bacteria to colonise the gut?
Enterobacteria, Bifidobacteria then firmicutes and bacteriodetes
why is it important to acquire the right sort of organisms?
dangerous if you acquire the wrong sort of bacteria too early
the right bacteria will create an environment suitable for them and prevent the growth of other pathogenic bacteria
what are the main ways you acquire microbiota?
ingestion and inhalation
Why do we understand very little about the microbiota?
most organisms cannot be cultured in the lab to be studied and sequenced
need integrated studies
what happens to the diversity of bacteria as you go down the GI tract?
it increases with the colon being the most diverse
how many bacteria are in the colon per human cell?
1.4 bacterial cells to 1 human cell
what are the protective functions of the gut microbiota?
exclude pathogens
compete for nutrients, receptors and between themselves
use up adverse nutrients for us
what are the structural functions of the gut microbiota?
Stimulate TLR to fortify gut barrier
Tightening cell junctions to prevent leaky intestines
stimulate IgA production
immune development
what are the metabolic functions of the gut microbiota?
GOOD:
use up carcinogens
making vitamins and vitamins precursors
fermenting what we can’t so we can use the product eg complex carbohydrates
BAD:
metabolising drugs preventing treatments being fully effective
What broader impacts can the microbiota have?
behaviour
anxiety
blood vessel formation
tissue homeostasis
eating habits
how many of our immune cells are associated with the gut?
30-40%
what are the 5 major cell type in immune sensing in the gut?
intestinal epithelial cells
M cells
Macrophages
Dendritic cells
Intra epithelial lymphocytes
what happens in normal immune homeostasis?
commensal bacteria stimulate PRRs and tighten tight junctions
what happens when a pathogen enters normal immune homoestasis?
dysregulation of TLR signalling
over response
loosening of junctions
bacteria cross the epithelial barrier
bacteria enter substital fluids and blood
what innate precautions do we have to prevent inappropriate immune activation?
More PRRs in deeper tissues as commensal are only at the apical surface
the commensal have low affinity for PRR as they don’t have adhesins
trapping of commensal by surface mucus
what PRR are in the intestinal crypt?
TLR2, TLR4, NOD1, NOD2
what do pathogens have that commensals don’t?
mucinases
Adhesins
Invasins
type 3/4 secretion system
haemolysins
exposure of TLR
Engagement of NLR
what keeps commensal from activating the immune system?
lack of virulence factors
less agonistic PAMPs
weak TLR activity
Life in biofilms on the mucus surface
controlled diffusion of PAMPs
why do we think pathogens evolved from commensals?
to overcome host defences
the immune system selects the pathogen with the ability to overcome its function
how can the bacterial pathogens overcome host defences?
modulate innate immunity
modulate adaptive immunity by diminishing recognition and memory
stealth to evade early immunity
secreted virulence factors subvert immune response by causing Cell and tissue lesions
how do pathogens modulate immune response?
avoid PRR
avoid death by Polymorphonuclear leukocytes
prevent pro-inflammatory signalling
inactivating immune cells
binding to inhibitory motifs
How does changing the acylation of lipid A avoid the immune system?
having 6 acyl chains will activate PRR
having 5 acyl chains has a much lower affinity for the PRR
all done through phase variation depending on temperature
how can type 3 secretion systems subvert immune responses?
injecting effector proteins
YOP proteins
Lethal factor
how can toxins prevent MAP kinase and NF-kB pathways activation by TLR?
suppress secretion of effector proteins
avoid immune detection by preventing signalling molecules
many different points of the pathway can be suppressed
what is the MAP kinase pathway?
Mitogen activated protein kinase pathway
what is the key point about the commensals and pathogen dynamic?
there are constant interactions and the decisions of tolerance of important
