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What are the three main ways an infectious agent can cause disease?

- contact with/entry into cells
- toxin release - exotoxins/endotoxins/enzymes
- induction of host responses - more damage e.g. suppuration, scarring, hypersensitivity (in some cases can be the main cause of disease).


Describe the four basic microorganisms that cause disease.

- 0.8-15 µm
- prokaryotes (lack membrane bound nucleus)
- single celled organism
- intracellular or extracellular

- 20-300nm
- require host biosynthetic and replicative apparatus for proliferation
- has to enter the cell

- 2-200µm
- eukaryotes (distinct nucleus)
- yeast or filamentous hyphae

- protozoa (1-50µm)
-- single celled eukaryotes
- Helminths (3mm-10m)
-- parasitic worms (multicellular organisms)


What are resident flora?

- not all microorganisms are pathogens
- microorganisms that live on or within the body in non-sterile areas
> skin
> mucous membranes
> GIT/bowel/rectum
> vagina

- not subject to inflammatory or immune attacks as long as skin and mucosa are intact

- balance of homeostasis to prevent infection/disease
-- antibiotic use can change resident flora
-- immunocompromise (AIDS, organ transplant) can lead to opportunistic infection by normal flora


What is a pathogen?

Disease-producing microbe

Disease is caused by
- contact/entry
- toxins
- host immune response

Pathogenicity (capacity to cause disease) is determined by
- virulence factors-determine how severe the disease is
- invasiveness, ability to evade the immune system, speed of multiplication, production of toxins, adherence to host cell, degree of tissue damage


What barriers are in place to block microbial invasion?

- epithelial cells with tight junctions
- air flow
- movement of mucus by cilia
- tears

- fatty acids
- enzymes/peptides
- pH
- surfactant

Normal flora - provide competition in that niche

Eyes - tears

Respiratory tract
- mucus
- cilia

Digestive system
- gastric acid
- bile
- enzymes
- mucus
- normal flora

- barrier
- normal flora

- flushing of urine
- acidity of urine

- pH
- normal flora


Describe the morphology of a normal stomach

Stomach broken up into areas which have particular cells in them.
- Cardia - mucin secreting cells, thick mucus material (at lower oesophageal sphincter)
- Fundus - acid and enzyme secretion (top lobe) - stuff that breaks down food
- (body) Corpus - acid and enzyme secretion
- Antrum - gastrin and mucin secreting cells (just before it moves into the duodenum)

cross section:
Longitudinal, circular, oblique muscles.
Muscularis mucosa
Mucosa with epithelial cells and gastric pits that produce acids/enzymes that are required to digest food


Do we get infection of the gastrointestinal tract?

The GIT:
- hostile environment
- acidic-secretion of hydrochloric acid: very low pH
- mucosal barrier to prevent autodigestion
- proteases
- historically considered to be a sterile environment
- however this environment can get disease e.g. chronic gastritis, peptic ulcer, gastric lymphoma, gastric adenocarcinoma


What is chronic gastritis?

Chronic inflammation of the stomach:
The presence of chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia

Few symptoms... nausea, vomiting, upper abdominal discomfort


What is a peptic ulcer?

- much more severe
- Ulcer - breach in the mucosa of the alimentary tract, which extends through the muscularis mucosa into the submucosa or deeper
- peptic ulcers occur in any part of the GIT exposed to acid/peptic juices
- epigastric gnawing, burning, or aching pain


What is gastric cancer?

Gastric adenocarcinoma
- most common malignancy of the stomach representing 90% of all gastric cancers and a leading cause of cancer related death

- derived from mucosa associated lymphoid tissue (MALT therefore MALToma)
- 5% of gastric malignancies are primary lymphomas
- dense lymphocytic infiltrate within the lamina propria
- chronic inflammation
- low-grade B-cell lymphoma can become high-grade


What is the dogma of 'no acid no ulcer'? How did this principle determine treatment and its outcomes?

- the cause of peptic ulcers was always believed to be too much acid
- if you can get rid of acid you won't have ulcer
- early treatment
-- targeted gastric acid secretion and mucosal defence mechanisms
--- inhibition of gastric acid secretion by selective blocking of the proton pumps of parietal cells
--- drugs that promote mucosal repair

- successfully heal ulcer
- ulcers tend to recur unless patient is maintained on acid suppression regime: drug company heaven - have to take my drugs forever
- why? treating the symptom but not the cause of disease


When was the role of infection in GIT disease theorised?

- 1984 paper published that stated:
"The bacteria were present in almost all patients with active chronic gastritis, duodenal ulcer, or gastric ulcer and thus may be an important factor in the aetiology of these diseases"
- considered that that infection may be important in the development of GIT disease


Which bacteria causes GIT disease?

- Helicobacter pylori


Who were the pioneers in discovering the role of helicobacter?

- 1892 - Italy - Giulio Bizzozero - noticed there were bacteria inside the stomach of dogs
- 1940s - Ireland - Prof. Oliver Fitzgerald - in people who had peptic ulcers/chronic gastritis there was a predominance of/could detect enzyme called urease - particular to people who have this disease
- 1958 - Greece - Dr. John Likoudis - gave himself antibiotics to treat a peptic ulcer and cured himself, also cured many people in the surrounding districts of peptic ulcers. Tried to extend his knowledge to the big cities of greece, "let's do a clinical trial" - but the establishment was very much of the opinion "no acid, no ulcer" and so wasn't able to get clinical trial up
- 1970s - China - Professor Shu-Dong Xioa - regional doctor treating people with antibiotics, people from local region benefitted
- 1982 - Dr Barry Marshall and Professor Robin Warren


Who finally got the role of helicobacter recognised in the medical community and how?

- Dr Barry Marshall and Professor Robin Warren
- Nobel Prize for Physiology and Medicine 2005
- for their discovery of "the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"
- who with tenacity and a prepared mind challenged prevailing dogmas
- Barry Marshall infected himself with H.pylori - gave himself a nice case of gastritis - took antibiotics and cured disease


What is the role of Helicobacter pylori in infection in GIT disease?

- Chronic gastritis: strong causal
- Peptic ulcer - strong causal - 1-10% of patients infected with H. pylori
- Gastric Adenocarcinoma - strong causal - 0.1-3% of patients infected with H.pylori, first bacterium classified as a carcinogen
- Gastric lymphoma - strong causal - <0.01% of patients infected with H. pylori


Describe the epidemiology of H. pylori infection

- Acquired-oral ingestion in early childhood
- 20-50% industrialised countries (santitation/hygiene)
- 80% developing countries
- not all people with H. pylori have gastritis/ulcers but all (almost) patients with gastritis/ulcers have H. pylori infection - why?


What determines who develops what disease?

- Virulence of the H. pylori strain
- Type and extent of the immune response
- Modulation cofactors
-- genetic
-- environmental


Describe helicobacter pylori

- non-sporing curvilinear gram-negative rod
- only human bacterium to persistently inhabit the gastric mucosa
- uniquely adapted to stomach environment - gastric acid and mucus

-spiral shape and multiple flagella confer corkscrew motility

acid resistance:
- urease (most abundant protein in H. pylori)
-- hydrolyses endogenous urea to ammonia and carbon dioxide
-- increases cytoplasmic pH
- Buffers periplasm
- chemotaxis
- enables H. pylori to reside in mucous layer (more neutral pH)

- attached to but does not invade the gastric mucosa
- most bacteria are free-swimming in the mucus, but a proportion is closely associated with the epithelial surface
- attachment not essential but part of pathogenesis


Describe the genetic diversity of Hp

- Enormous genetic diversity
-- genetic drift
-- high mutation rate
-- natural transformation competence-exchange of DNA


What is BabA?

- blood group antigen-binding adhesion
- facilitates adhesion to gastric epithelial cells
- Cell notices that it has been bound to, and will respond: epithelial proliferation and inflammation


What is Vac A ?

- vacuolating cytotoxin
- protein = 95kD
- epithelial cell membrane, forms voltage-gated channel
- forms hexameric pores, which are selective to anions and small neutral molecules, including urea
- endocytosed and affect endosomal compartments (vacuoles) and mitochondria (cytochrome c release and apoptosis)


What is the CagA gene?

- cytotoxin-associated gene A
- part of cag pathogenicity island
- gene product (120-145 kD protein) strongly associated with peptic ulcer, gastric duodenal cancer
- cag pathogenicity island:
-- large section of DNA that can be acquired by bacterial species
-- stains may be Cag+ or Cag-
-- contributes to pathogenicity
-- in some countries Cag+ strains are virtually ubiquitous

- with Cag PI it is able to punch a hole into the cell, and through that put the CagA into the cell
- CagA causes changes in cellular function, affects proliferation and epithelial barrier that can contribute to disease
- can lead to proliferation and motility of the cell
- affect cytoskeleton
- induce apoptosis
- cause faulty apical junctional complex allowing for paracellular leakage


What is the host response to H-pylori infection?

- All H. pylori strains induce a marked immune response
- Host immune response is generally ineffective in clearing the infection
- H. pylori has developed methods to evade immune response
-- changes in LPS and flagellin (PAMPS) reduced recognition by innate immune response (PRR/TLR)
-- inhibit NO production by macrophages
-- enzymes that combat bactericidal oxidative stress
- immune response is important to pathogenesis
- inflammation is greater in strains that express specific virulence factors
- infection with H. pylori will give you a chronic inflammatory response


What is the specific immune response and pathogenesis?

- H. pylori is an extracellular pathogen
- induces a strong humoral immune response
- should result in Th2-cell help
- but response is generally Th1-cell - skewing of immune response


What is the pathogen-host interaction?

- if you end up with a Th-1 response you will end up with a severe chronic gastritis because it is not as effective at clearing the infection
- Th-2 = mild gastritis


How does H. pylori contribute to the development of peptic ulcer?

- depends on whether you can maintain the balance of defensive forces against damaging forces
- Hp increases susceptibility to peptic ulcer
- disruption of gastric and duodenal mucosal defences vs.
- gastric acidity


What is peptic ulcer disease?

- degradation of the epithelial layer below the mucosa


What are the consequences of severe gastritis?

- if you have inflammation in the body corpus - these are the cells that produce acid, so damaging these cells will result in less acid production --> gastric atrophy --> more likely to get gastric ulceration

- in contrast: if gastritis is down in the antrum - more acid in stomach - these are not the cells that produce acid - ulcers tend to be in duodenum


Describe gastric ulcers caused by H. pylori infection

- associated with pan gastric inflammation
- reduced or normal acid secretion
- dense colonisation and inflammation
- H. pylori compromises mucosal defenses leading to epithelial damage


Describe duodenal ulcers caused by H. pylori infection

- inflammation of the gastric mucosa in non-acid secreting antral region of the stomach
- increased stimulation of acid secretion from the less affected proximal acid secreting fundus mucosa
- may cause gastric metaplasia into duodenum in response to increased acid (enabling H. pylori colonisation)


What are the consequences of H. pylori infection?

- High acid = duodenal ulcer
- corpus predominant = gastric ulcer
- further consequences = cancer


How does H. pylori infection cause gastric cancer?

Gastric adenocarcinoma
- epithelial proliferation in the background of chronic inflammation
- pangastric or corpus-predominant gastritis
- associated with gastric atrophy and intestinal metaplasia
- carcinogenesis associated with gastric atrophy
-- reactive oxygen and nitrogen species associated with inflammation
-- possibly other bacteria within the the now achlorhydric stomach

Gastric lymphoma
- normal stomach does not have Mucosa-associated lymphoid tissue (MALT)
- MALT acquisition depends on infection with helicobacter species
- Transformation into low-grade extra-nodal B cell lymphoma
-- direct antigen stimulation by H. pylori
-- mutations caused by oxidative damage


What host genetic factors are involved in predisposing to gastric cancer?

- host pro-inflammatory cytokine variations predispose to adenocarcinoma
- cytokine gene polymorphisms
-- IL-I gene cluster
-innate immune response gene polymorphisms
-- TLR
- HLA polymorphisms


What are some other causes of peptic ulcer disease?

- not all people with H pylori have gastritis/ulcers but all (almost) patients with gastritis/ulcers have H.pylori infection
- gastric hyperacidity - strongly ulcerogenic
- chronic use of non-steroidal anti-inflammatry drugs especially aspirin
- use of corticosteroids
- tobacco smoking
-- impairs mucosal blood flow
-- affects healing
- alcohol - peptic ulcers


What is the treatment and prevention of the disease?

- the goal for people with H. pylori is complete eradication (cure)
- antibiotics + proton pump inhibitor to reduce acidity
- challenges:
-- antibiotic efficacy in acidic environment
-- effective vaccine development and induction of effective immune response
-- the role of H. pylori infection in other disease
-- gastroesophageal reflux disease