Lecture 4 - Infection - Helicobacter pylori Flashcards
What are the main mechanisms of infectious agents causing disease?
- Entry
- Toxins:
• exotoxin
• endotoxin
• enzymes - Immunopathology
How big are bacteria?
Generally
1-15 microns
What are the various organisms that can cause disease in human hosts?
Bacteria Viruses Fungi Parasites (prions)
What are the ‘non sterile’ areas on our body?
What does this mean?
Our body is largely colonised by micro-organisms This is our microflora • skin • gut • mouth • nose • vagina
Under which circumstances will microflora cause disease?
- Antibiotic use wipes out microflora, pathogens can now colonise
- immunocompromise
- damage to barriers
What factors determine virulence?
- virulence factors
- ability to evade immune system
- ability to spread
What are some barriers to infection?
Mechanical: • epithelium • flushing (urine, tears) • mucociliary elevator Chemical: • lysozyme • phospholipase • pH • surfactant • mucous Normal flora • occupying the niche
What are the various sections of the stomach?
- Cardia
- Fundus
- Corpus
- Antrum
What is the function of the cardia of the stomach?
Mucous secreting cells
What is the function of the fundus of the stomach?
Acid and enzyme secretion
What is the function of the corpus of the stomach?
Why is this significant? Explain the consequences
Acid and enzyme secretion
- Cardia is inflamed
- Decreased acid production
- Gastric atrophy
- Gastric ulceration
What is the function of the antrum of the stomach?
Why is this significant?
Mucin and gastrin secretion
- Antrum is inflamed
- Increased acid production (because these cells produce gastrin)
- Risk of duodenal ulcer
What is the tissue structure of the stomach wall?
Mucosa: • Epithelium • Lamina propria • Muscularis mucosae • + Gastric pits
Submucosa
Muscularis propria
• Oblique
• Circular
• Longitudinal
Serosa
Which is the most prevalent stomach cancer?
What is another, less common one?
Gastric adenocarcinoma (90%)
Gastric lymphoma (a MALToma, 5%)
How were peptic ulcers treated originally?
How did this fall short, and why?
Blockage of gastric acid secretion
(blockage of proton pumps in parietal cells)
Ulcers would return unless acid suppression was continued. This is because the cause was not removed
What is the cause of peptic ulcers?
Helicobacter pylori
H. pylori was the first bacterium to be classed as a…
carcinogen
What diseases does H. pylori cause?
- peptic ulcer
- chronic gastritis
- gastric adenocarcinoma
- gastric lymphoma
Which countries are most affected by H. pylori infection?
Unindustrialised countries
How does H. pylori enter the system?
Oral ingestion, usually in childhood
How is H. pylori acid resistant?
Urase
• produces basic compounds (ammonia, urea)
• buffers the cytoplasm
Where does H. pylori hang out in the stomach?
• Adheres to the mucosa
(does not invade)
• In the mucous
Why is H. pylori so genetically diverse?
- genetic drift
- v. competent at transformation
- high mutation rate
What are the virulence determinants of H. pylori?
vacA
babA
cagA
What is babA?
Protein allows adhesion of bacterium to gastric epithelium
What is cagA?
Gene that codes for a protein that is strongly associated with
• peptic ulcers
• gastric cancer
through biochemical pathways in the host cell
The gene is translocated into the host cell
What are some of the effects of the biochemical changes in response to cagA?
- paracellular leakage of gastric mucosa
- motility
- apoptosis
- proliferation
- cytoskeletal changes
Describe very generally the immune response to H. pylori
Considerable immune response launched
Ineffective at clearing the infection
How does H. pylori avoid immune responses?
- altered PAMPs that aren’t recognised by PRRs
* Inhibit respiratory burst by macrophages
(General Question)
What are some important PAMPs in bacteria?
- flagellin
* LPS
Describe what happens when H. pylori initially adheres to epithelial cells
Cytokine release
→ neutrophil infiltration
Who discovered the cause of peptic ulcers?
Why is this important?
Dr Barry Marshall and Robin Warren
They challenged the accepted dogma despite criticism, and went on to win a Nobel prize for it
What is the symbol for macrophages?
Mφ
What are the later immune responses to H. pylori infection?
- Adaptive (B and T lymphocyte) induction
- apoptosis of epithelial cells
- disruption of mucous layer
- increased gastrin released, increased acidity
Is H. pylori intra- or extracellular?
What does this mean for the immune response?
Extracellular
• Humoral response is important
• Th2 is important
Why don’t all people with H. pylori get peptic ulcers?
• different strains
• different host immune responses
• genetic, environmental cofactors
→ NSAID use, smoking, alcohol
H. pylori was the first bacterium to be classed as a…
Carcinogen
What causes gastritis?
Disruption of normal balance between mucosal defences and damaging forces
H. pylori is often responsible for this disruption
Gastritis often leads to…
Peptic ulcers
How can host polymorphisms affect predisposition to cancer?
Polymorphisms in genes for immunity • HLA • cytokines etc. affect the host response, and thus affect predisposition
What is vacA?
Pore proteins that affect endosomal compartments such as vacuoles
Endosomal compartments, such as the mitochondria.
Leads to release of cytochrome c from the mitochondria → apoptosis
How does smoking affect predisposition to peptic ulcer?
Impairs mucosal blood flow, and thus impairs the healing process
How is H. pylori infection treated nowadays?
- Antibiotics
* proton pump blocker to reduce acidity
What defences against infection are there in the stomach?
Acid
Proteases
Epithelial & mucous barrier
What is a peptic ulcer?
Breach of the mucosa
Extends from mucosa through to submucosa or deeper
What are the symptoms of a peptic ulcer?
Epigastric gnawing
Burning pain
Where do peptic ulcers occur?
Anywhere in the GIT exposed to gastric acid
Why is cure of infection a challenge?
• Antibiotic activity is altered at stomach pH
Where do H. pylori bacteria all attach?
They don’t all attach, but some do attach to the gastric mucosa
What are the causal factors of Duodenal ulcers?
What are some other sequelae?
Increased acid in duodenal portion of small bowel
This is a result of inflamed antrum (see below)
- Inflamed antrum
- Increased acid production
- Acid in duodenum
- Metaplasia of duodenal cells to gastric mucosal cells
- The cells can be infected: colonisation of duodenum with H. pylori
Why does chemotaxis confer stability in the stomach to H. pylori?
It can move to the more pH neutral areas (the mucous)
H. pylori only bind to…
Gastric mucosa (in the stomach)
