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

lecture 4 Flashcards by Molly Fowler

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).

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Describe the four basic microorganisms that cause disease.

Bacteria

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

Virus

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

Fungi

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

Parasites

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

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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

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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

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What barriers are in place to block microbial invasion?

Mechanical

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

Chemical

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

skin

barrier
normal flora

urogenitory

flushing of urine
acidity of urine

vagina

pH
normal flora

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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.
Submucosa
Muscularis mucosa 
Mucosa with epithelial cells and gastric pits that produce acids/enzymes that are required to digest food

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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

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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

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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

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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

Lymphoma

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

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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

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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

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Which bacteria causes GIT disease?

Helicobacter pylori

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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

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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

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

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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

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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?

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

Describe helicobacter pylori

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

motility:
- 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)

adhesion

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

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

What is BabA?

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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 ?

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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?

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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?

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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