mucins and mucus Flashcards
what are the 2 layers of the mucus barrier?
- mucus barrier on top = gel-like, highly organised, responsive to environment, mesh like (made of mucin glycoproteins)
- epithelial glycoprotein layer = sugar-rich, on apical cell surface
the mucus layer is home to what kind of microbes?
commensal
what do goblet cells make?
mucins
what pathologies can happen if there is too little mucus?
- gastric/duodenal ulcers
- ulcerative colitis
- crohn’s disease
- dry eye
- xerostomia (dry mouth)
what pathologies can happen if there is too much mucus?
- asthma
- cystic fibrosis
- chronic obstructive pulmonary disease (COPD)
what does mucus line?
the epithelial surfaces that are in contact with the environment for the entry, release or exchange of materials
eg. mouth, resp tract, GI tract, urine genital tract, eyes and ears
what are some challenges of the GI mucosal interface?
- complex range of functions including secretion and absorption
- a very large SA exposed to adverse biological, chemical and physical challenges
- non-sterile and potentially exposed to microbial pathogens and eukaryotic parasites
- provides a niche for commensal bacteria (1012 organisms/gram in the colon)
- microbial content and diversity is determined by the environment and thus alters with changes in the mucus
both layers in the mucus have the same molecules but the open layer molecules have been what?
degraded by proteolytic enzymes to make it more open
where can bugs live freely?
the loosely adherent mucus layer
what is the dual function of the intestinal mucus barrier?
home for the mcirobiota and protection against infection
what happens when the inner adherent layer breaks down?
the commensal bacteria can become pathogenic
what are the properties of the GI tract mucus?
- resistant barrier (physical and chemical)
- viscous highly hydrated layer
- prevents dehydration of mucosal surfaces, provides lumbricals on for movement of liminal contents in the gut
- porous to large macromolecules up to very small particulate matter (not cellular microbes)
- allows absorption and secretion to continue
- self organises around particulate matter and promotes removal (mechanism is unclear)
what is mucus made up of and what kind of material is it?
viscoelastic material — has the viscous behaviour of a liquid and the elastic properties of a solid
- 90% : water and ions
- 5-10% : proteins (glycoproteins)
- 1-5% : mucus glycoproteins (mucins)
what are the key structural components of the mucus barrier?
mucins
where are mucins stored?
in goblet cells in storage granules — mucins can be released to produce a layer when there is a challenge
what is the family of gel-forming mucins?
- 5 identified members - MUC
- MUC 2, 5AC, 5B, 6 + 19
- share same generic structure - all very similar
what MUC mucins are found mainly in the stomach vs rest of intestine?
stomach = MUC5AC + MUC6
rest of intestine = MUC2
what happened in rats with no Muc2?
- no intestinal mucus barrier
- infection (bacterial and parasite)
- increased susceptibility to colitis and tumours
mucin size?
ENORMOUS
how does increasing the number of mucins affect the mucus?
more mucins = thicker mucus
mucins are repeating units, linked end to end via what?
disulphide bonds
what are the central regions of mucins covered in?
sugars
mucins are repeated what?
serine/threonine
what sugars are attached to the middle of mucins?
N-acetylgalactosamine, N-acetylglucosamine, galactose fucose and sialic acid
the sugars in mucins have receptors for what?
pathogens
how do mucins underpin protection?
- space filling — entanglement of large polymers hydrogel formation
- pathogen binding/evasion
cross links vs entanglement in mucins
- cross links are more permanent — thicker mucus
- entanglement makes a thinner, dynamic, transient mucus
the gut has more cross links on top of entanglement — therefore more protective (than eg. in lungs)
what is the glycocalyx?
a dense, gel-like meshwork that surrounds the cell, constituting a physical barrier for any object to enter the cell
- on apical cell surface
- sugar rick
- defence
what are proteins called when they are bound to a sugar?
lectins
how can mucins act as decoys?
- pathogen breaks throguh the mucus layer adn can bind to the same sugars but on the apical surface of the cell
- it is then shed and acts as a decoy to remove potential for infection
most mucosal bacterial pathogens are ______ - allows them to swim in mucus
flagellated
many mucosal pathogens produce enzymes to degrade the ____ and thereby disassemble the mucus barrier
mucins
bacteria produce soluble toxins that can do what?
kill epithelial cells and/or arrest intestinal cell division
many pathogens attach to the apical surface of the epithelial cells and do what?
inject bacterial toxins
many mucosal toxins do what between adjacent epithelial cells?
disable tight junctions
pH, bacteria growth and antibiotics?
increasing the pH raises growth of bacteria, but antibitoics become more effective when bacteria is in growth phase
what is the bacterium causing peptic ulcer disease?
Helicobacter pylori
what part of the stomach does H.pylori affect?
infects the lower part of the stomach, antrum
what % of the world’s population are chronically infected with H.pylori?
roughly 50% — majority are asymptomatic or have very mild symptoms
- decreased to 20-30% in the western world and up to 90% in the developing world
infected individuals with H. pylori can develop what?
chronic inflammation with persistent infection (gastritis)
what are serious pathologies resulting from chronic gastritis?
- gastric and duodenal ulcers
- gastric carcinoma (5% of the world cancer burden)
adhesin genes (colonisation) — glycan binding proteins
what are there?
SabA gene — sialic acid binding adhesin
BabA gene — Lewis b binding adhesin
—> adhesins specific for binding sugars — colonise
what is the CagA gene?
- CagA pathogenicity island (epithelial pathology)
- type IV secretion system, disabling of epithelial tight junctions
what is VacA gene?
- CagA pathogenicity island (epithelial pathology)
- cytotoxin
MUC5AC vs MUCA6 location in the stomach
MUCA6 closer to cell surface
H. pylori has adhesins for ____ on cell surface glycoproteins adn glycoplipds found on the ____ epithelial surface = ___ and ____
- glycan structures
- gastric
- BabA and SabA
MUC5AC vs MUC6 function
MUC5AC = binding
MUC6 = growth inhibition
both in mucus layer
bug binds to MUC5AC and is kept at a distance so can’t bind at epithelial surface
provide 2 layers of defence
what is a transmembrane mucin similar to MUC5AC?
MUC1
MUC1 function
is shed from the cell surface (acts as a decoy) when H. pylori binds
