lecture 10 Flashcards
humoural arm and innate immunity toxic slime, punching holes and ringing alarms
why do we rely on our innate immune system?
bacteria grow way to rapidly and so the adaptive immune response would be too slow
we rely on our innate immune system for protection in the first few critical hours after pathogen detection
what are the three lines of innate immune system defence?
- barriers - physical and chemical
thick layer of keratinized dead cells on the skin
tight junctions between epithelial cells
acidic stomach pH
mucus layers - cell intrinsic responses
pathogen induced phagocytosis
degradation of dsrna - specialised proteins and specialised cells
professional phagocytes like neutrophils and macrophages
natural killer cells
the complement system
–> these are not specific to particular pathogens/ non-specific rapid innate responses
define the role of mucus layers
the mucus layer on moist epithelial surfaces protects against microbial mechanical and chemical insults
(hagfish are all shaped marine jawless animals that produce mucus layers on their skin when triggered)
structure of the mucous layer
it is made from secreted mucins and other glycoproteins
it’s slippery which makes it hard for pathogens to attach to mucus coated epithelia
ethereal cells have beating cilia which can facilitate clearing of pathogens
mucous is slippery because the proteins are covered with soluble carbohydrates which means that there is a water shell around each one of the mucin molecules
define the defensins of mucus layers
they are small positively charged antimicrobial peptides
they have hydrophobic or amphipathic helical domains
they are very simple structures of coils or flattened beta sheets
coils are amphipathic so they have different charges on different sides of the coil
beta sheets are hydrophobic and interact with cell membranes
role of defensins
defensins have wide-antimicrobial activity and can kill or inactivate: gram positive and gram negative bacteria fungi (like yeast) parasites (like protozoa and nemaotdes) enveloped viruses (hiv)
there are many classes of defensins so there is a wide repertoire of targets
define an enveloped virus
Enveloped virus is a virus that makes new viral particles and borrows part of the cell membrane of the host cell so that it has its own lipid membrane around it
how defensins kill
They have hydrophobic patches so can interact with membranes and enter it to destabilize that membrane, leading to cell lysis
Since the coils in the defensins have the separation of charges, so the positive charge can interact with the backbone of dna and rna
→ we’re not sure how they work, this is just a guess
how do defensins lyse pathogens but not ouor own epithelial surfaces?
they are much more active on membrane that do not contain cholesterol (our membranes contain cholesterol)
More cholesterol, the more resistant the cell is to defensins
it is hard for an organism to mutate to get defensins
define PAMPs (pathogen associated molecular patterns
pathogens do occasionally breach the epithelial barriers.
the innate immune system recognises molecules (pathogen associated or microbe associated immunostimulants) that are common to many pathogens, but essentially absent in the host.
an alternative name is PAMP, referring to an older view that the innate immune system recognises patterns in pathogens
examples of PAMPs
things that are completely foreign to us are recognised as PAMPs by our innate system
fMet peptidoglycans bacterial flagellae lipopolysaccharide LPS mannans, glucans, chitin from fungi motifs in bacterial / viral dna
pattern recognition receptors found in? (2)
toll-like receptors recognise these PAMPs (LPS, CpG motifs, flagellae) and stimulate an nflammation as a cry for help
Receptors in the blood recognise the peptidoglycans
define complement
about 20 soluble proteins that are activated sequentially upon infection
how does complement activation target pathogens for lysis?
there are 2 pathways:
- lectin pathways (Lectin is any protein that can bind to a sugar. Lectin receptors will bind any fungi that carries sugar on their surface)
- alternative pathway (pathogen surfaces)
describe the complement system
it is a set of pro enzymes where the activation of one leads to the activation of another etc. They are proteolytic
C2 is cleaved, when activated will cleave C4, cleaves C3)
C3b targets the pathogen and binds to its membrane and C3a calls for help
what does the binding of C3b to the pathogen membrane cause?
pathogen bound C3b stimulates a local cascade of reactions (C5 to C8) at the marked membrane
C9 is inserted into the membrane
a c9 pore breaches the membrane c9 multimers form a membrane-attack complex
pathogen lysis
define toll-like receptors
toll is a trans-membrane protein with a large extracellular domain with repeating motifs (leucine-rich repeats)
These can bind many other proteins
binding to pathogenic fungi sends a signal to the nucleus
antifungal defensins are expressed
toll-like receptors have the same overall structure and do a similar job
where are toll-like receptors found?
most TLRs are o the cell membrane of epithelial cells and macrophages, dendtritic cells and neutrophils
toll-like receptors as an alarm system
TLRs bind PAMPs
signal the nucleus
result in transcription of hundred of genes (especially inflammation genes)
explain how defensins and TLRs are ancient immune system components
proteins related to TLRs and defensins are apparently involved in innate immunity in all multicellular organisms
for resistance to fungal, viral and bacterial pathogens, plants require:
membrane receptors, leucine rich repeats and domain homologous to the cytosolic domains of tlrs
this suggests that rlrs and defensins pre-date the ancestral split between animals/plants/fungi
gonorrhoeae
why is it a a facultatively intracellular organism
causative agent of the sexually transmitted infection gonorrheae
- the drip (refers to the dripping purulent discharge from the urethra)
- the clap (derived dfrom clapie meaning brothel)
It’s a facultatively intracellular organism - important because it can hide in our cells and infect our body
gonorrhea symptoms
most are asymptopmatic
purulent foul smelling discharge
inflammation
painful urination
urethritis
males (10% asymptomatic) get prostatitis and orchitis
females (80% are asymptomatic) get pelvic inflammatory disease, probably infertility
gonorrhoeae prevalence
us data up to 2016, giving a healthy people target for 19 cases per 100 000 people in 2010
this was not reached
transmission rates
a female with an infected man has a 50% chance of infection
a male with an infected woman has a 20% chance of infection
evasion of the innate immune system: gonorrhoeae
the capsule lacks LPS, instead has LOS lipooligosaccharide
it can utilise host derived sialic acid to sialylate its LOS
with sialylated LOS, they are less invasive than those with nonsialylated LOK, but are more resistant to the bactericidal effects of serum
this is because human cells also display sialylated glycoproteins, so they can masquerade as us and evade our immune system
summary
If a pathogen interact with a TLR, we get expression of interferons and ring alarm bells to cause inflammation
The pathogen surface can be recognised by the complement surface, where C3 is cleaved and a part of it is bound to the surface, another part causes inflammation
In our toxic slime, we have defensins - direct membrane attack
