lecture 12: everybody laughed

what are stomach ulcers?

is a chronic debilitating condition that can be extremely painful and can lead to blood loss, peritonitis and death if perforation occurs

what is the treatment of stomach ulcers?

• modifications to diet, antacids

• sometimes vagotomy or cutting the vagus nerve because it is involved in signaling acid production in the stomach and surgical resection of the damaged area of the stomach

how do ulcers start off?

as an erosion of the mucosa and extends into the submucosal layer

why did doctors never really took peptic ulcers seriously?

because they believed that the stomach was too acidic to support any bacteria

what were Dr. Warrens observations?

• he often observed large numbers of helical, flagellated bacteria in those with history of ulcers

why did no one believe them?

when they tried to inoculate animals, they didnt get any progress

• Marshall actually drank the culture, had suffered for a week and cured himself with antibiotics

what are helicobacter pylori?

• are gram negative curved rods with spiral morphology but can adapt coccoid morphology

• microaerophile

• have several polar flagella and are highly motile

• expresses LPS in the outer membrane, but has low endotoxin activity

• the O antigen portion of the LPS is heavily fucosylated and antigenically similar to the human lewsi blood group antigen

how did H.pylori survive in the stomach pH

• it expressed urease enzyme that converts urea into CO₂

and ammonia

• ammonia is basic so. it acts as a neutralizer which was sufficient enough to alter bacteria’s microenvironment

how is H.pylori able to cross the mucus layer of stomach

• the ph below the mucus layer is much higher than in the lumen in the stomach

• H.pylori can sense the pH gradient and seek lower protons

• urease activity raises pH locally and causes “de-gel” of the mucus layer

• then the flagella drives the bacterium thru the softened mucus layer and onto the surface of gastric epithelial cells

after getting thru the mucus layer, how does the bacteria attach to the epithelial cells?

• it produces adhesins

• that help attach to the gastric mucosal cells

• one of them is BabA which binds to the Lewis B antigen

• another one is SabA that binds to sialyl Lewis X antigen

what is cag pathogenicity island

is a region of H.pylori DNA that can encode a number of additional virulence factors that enhance the disease causing potential of the bacteria

• it has a type IV secretion system that allows them to inject cag pathogenicity island encoded factors directly into the gastric epithelial cells

H.pylori virulence factors: diamino pimylate

• it acts as a PAMP that is sensed by the cytoplasmic pattern recognition receptor NOD-1

• this leads to NFkB activation which activated genes for pro- inflammatory cytokines, particularly neutrophil chemoattractant

what is CagA

is a cytotoxin associated protein A

• is undergoes tyrosine phosphorylation by Src and Abl once inside the cell

• then it acquires the capacity to interact with SHP2

• and then interacts with PAR1b and MAPK and inhibits their activity

what is Vac A toxin

is an 88kDa protein that is secreted as a monomer

• if forms a hexamer rosette that inserts into membranes

• late endosome specifically, forming a chloride channel leading to osmotic swelling of the vesicle

• can also perforate mitochondria triggering apoptosis of infected cell, that disrupts epithelial barrier that allows acsess to additional nutrients

• disrupts antigen presentation

what are the consequences of interactions of virulence facors?

• epithelial cells lose shape and ability to form junctions with each other, meaning the integrity of mucosa is lost

• this gives cells properties of cancer

• pro-inflammatory cytokines call other cell types to release toxic factors meant to kill bacteria

what does the CagA expression by H.pyori does?

it induces a hummingbird phenotype on gastric epithelial cell

what are the dynamics of ulcer formation?

• the increase in pH from bacterial urease decreases viscosity of mucus, making it wash away and exposing the mucosa to stomach acid and direct attack from pepsin protease

• CagA causes changes to epithelial cell morphology disrupting the integrity of the outermost layer of cells, allowing penetration of acid and protease into lower layers

• meanwhile, the bacterial cell wall components through activation of NOD1 recruit neutrophils into the deeper tissues, they release ROI and tissue-remodeling enzymes which attempt to kill bacteria and do further damage

• this is a vicious cycle and prevents regeneration and healing and may progress to perforation

how can H.pylori infection lead to cancer?

• CagA interacts with and is phosphorylated by known cellular protooncogenes

• CagA interacts with growth factor signaling components such as c-MET involved in carcigogenesis \

• CagA perturbs cell cycle control and up regulated matrix metalloproteinases, which cancel cells use to be invasive

• CagA interferes with function of tumor suppressor gene p53

• chronic inflammation from immune response causes release of ROI that can damage DNA

• accumulation of mutations combined with growth factor signaling from CagA is a recipe for carcinogenesis

why isnt everyone infected with H.pylori?

• there is a lot of genetic variability with H.pylori and not all strains possess CAG pathogenicity island and there are also polymorphisms in the various virulence factors

• there are genetic variations in the regulation of some pro inflammatory cytokines that appear to pplay a role in the infection