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Flashcards in Protection From Pathogens Deck (13):

What are the defence mechanisms of a mucosal surface?

Mucosal surfaces are exquisitely adapted to deal locally with most environmental insults and pathogenic challenges.

Most are lined with a single layer of epithelial cells which delineates the outside world from host tissue responses.


What are the features of the GI Tract?

Pre-epithelial 1: Stomach:
Protection of gastric epithelium by mucus and secretion of neutralising bicarbonate by specialised epithelial cells, creates a descending pH gradient down the crypts.

Pre-Epithelial 2: Mucus:
Mucus is secreted by goblet cells, it has several essential functions:
- Lubricant
- Prevents mechanical stress on epthelium
- Thick layer provides stable microenvironment
- Prevents invasion
- Essential environent for microflora
There is a firmly adhered mucus layer and a loosely adherent mucus layer all throughout the GI.
- corpus: approx. 100 ug thickness of each
- antrum: approx. 150 ug thickness of each
- duodenum: approx. 200 ug of loose mucus and approx. 20 ug firmly
adhered mucus descending into the villi
- jejunum: approx. 150 ug of loose mucus and approx. 20 ug firmly
adhered mucus descending into the villi
- ileum: approx. 450 ug of loose mucus and approx. 50 ug firmly
adhered mucus descending into the villi
- colon: approx. 750 ug of loose mucus and approx. 100 ug firmly
adhered mucus

Pre-Epithelial 3: Microbiome Skin (including ears!)
- In GI Tract bacterial cells outnumber our human cells by 10 to 1. The
microbiome is predominantly bacteria, but also includes fungi
and viruses
- Your microbiome is unique. There is a greater abundance of these
species in each end of the GI (mouth and anus)
- The absence of gut bacteria affects:
- Behaviour
- Gut homeostasis
- Immune response under stress
- Body weight
- Brain development and gene expression

Pre-Epithelial4: secretory IgA:
IgA is a mucosal- specific antibody responsible for primary defence against bacteria. It is the most common immunodeficiency, with 1 in 700 Europeans are IgA being deficient. However, many have no symptoms…. BUT
- IgA deficiency often presents with IgG2 deficiency
- Increases susceptibility to certain bacteria
- IgA deficient patients suffer more episodes of:
- bronchitis
- pneumonia
- chronic diarrhoea
- conjunctivitis
- sinusitis


How are H. Pylori infections of the gut diagnosed?

H pylori strongly associated with gastric and (later) duodenal ulcers.

H. Pylori penetrate the mucosal layer. Once on the epithelial surface they produce ammonia which neutralises the gastric acid. There they cause mucosal damage by bacterial mucinase, etc. The gastric acid and protease (eg pepsin) released cause inflammation of the GI epithelium. This causes mucosal cell death by cytotoxins and ammonia.

Production of ammonia by H pylori forms the basis of the carbon-13 urea breath test. This is the most non-invasive test for presence of H pylori before and after treatment.


What is cystic fibrosis?

A severe disease causing excessive mucus production in the lungs and pancreatic ducts.

Life expectancy 30 years.

A protective layer of mucus is essential for health


What is E. Coli?

E. Coli is a commenal bacterium
Species is highly diverse. Acquisition of virulence genes can lead to pathogenicity. World's largest E. coli outbreak kills 14 in Germany (May 2011)

3,500 infected, 855 developed rare haemolytic uraemic syndrome
53 died.

Enteroaggregative strain of E. coli had acquired Shiga toxin which caused HUS.


What is the NIH Human Microbiome Project?

2013-2015: Integrated dataset from microbiome and host
for microbiome-associated diseases.

Sequenced the microbiome from 300 young healthy volunteers
Samples taken from 5 sites (nose, ears, skin, urogenital tract, gut)
To try and define ‘healthy’ flora
Conclude: healthy flora is diverse…

Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis


What is a clostridium difficile infection?

The leading cause of health care-associated infectious diarrhea (1,646 deaths in England and Wales 2012). Caused by a spore-forming gram positive bacillus which is part of normal healthy flora in 4% of healthy individuals.
- Spores are resistant to stomach acid
- Once in intestine, germinate and move into vegetative state

However, 20-25% of C. difficile strains do not cause disease. Virulent strains release toxins A & B, leading to severe damage of gut lining. If this leads to fulminant colitis, mortality rate 35% - 80%
- Strain NAP-1 or B1 associated with severe colitis
- Hyperproduction of Toxins A & B
- Cannot inhibit toxin production during growth phase, so 10x toxin
- Higher rate of germination from spores

Patients very quickly go from symptomatic to asymptomatic. Clinical features include:
- Severe diarrhea
- Severe abdominal pain
- White blood cell count >15000 cells/ul
- Toxic megacolon
- Organ failure

Virulent strains are most often found in a health care setting, where spores are easily spread. Also recent administration of antibiotics has been proven to be a key risk factor.
- antibiotics cause a change in flora that facilitates colonization &

Virulence is evolving - total cases rose dramatically 1999-2005, with reported infections still on the rise, despite reported deaths falling.
- Considered a new ‘epidemic’??


How is C. Difficile tested for?

OpGen C. Difficile DNA complete test: Complete hyper-virulence profile:
- toxin A ⬇️
- toxin B ⬇️ Increasing
- binary toxin ⬇️ Severity
- B1/NAP1/027 ⬇️
Real-time PCR Direct detection from stool
Results in one day
Additional epidemiological and genomic analysis available


How is a faecal transplant used to treat recurrent C. Difficile infections?

Even if antobiotics are given to kill the c.dif the spores will still remain allowing for recurrent infections.
Only way to treat this is to completely replace the patients microbiome

- donor faecal sample is filtered
- administered by enema, transcolonic infusion, nasoduodenal or
nasogastric infusion

1.1Current evidence on the efficacy and safety of faecal microbiota transplant for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
1.2This procedure should only be considered for patients with recurrent C. difficile infections that have failed to respond to antibiotics and other treatments.
1.3Clinicians should ensure that a confidential record is kept of the donor and recipient of each faecal microbiota transplant.
1.4NICE encourages further research into faecal microbiota transplant for C. difficile infection, specifically to investigate optimal dosage, mode of administration and choice of donor


How is bacteriotherapy used to treat recurrent C. Difficile infections?

In a new study, researchers used mice to identify a combination six naturally occurring bacteria that eradicate a highly contagious form of Clostridium difficile, an infectious bacterium associated with many hospital deaths. Three of the six bacteria have not been described before. This work may have significant implications for future control and treatment approaches.


What are the features of stratified squamous epithelium?

- Mechanical friction - rubbing and physical trauma from external
- Chemical damage - environmental and internal chemicals/
compounds degrading epithelial lining
- Lining of the esophagus - protection of the esophagus from stomach
acid, non-keratinized, mucousal cell layer
- Alveoli - cell layer essential for gas exchange, also a protective layer
against air-born pathogens/toxic gases


What are the features of the bladder?

There is no mucosal layer in the bladder


What are the features of Pseudostratified epithelium?

Eg bladder, trachea
Dome shaped relaxed surface cells and a transitional epithelium
Designed to respond to mechanical stretching