Enteric Infections and Pathogenesis of Infective Diarrhoea

Question 1

What bacteria cause enteric infections?

Answer 1

E. coli (EHEC, ETEC, EIEC, EPEC)

Salmonella

Shigella

Yersinia enterocolitica

Vibrio cholera

Non-cholera vibrios

Campylobacter

Bacillus cereus

Clostridium perfringens

Clostridium difficile

Staph aureus

Question 2

What are potential outcome of enteric infections?

Answer 2

Can lead to an inconvenience

Can have a serious impact

Can lead to death.

Prognosis is worse in impaired host (immunocompromised/malnourished/extremes of age)

Question 3

What influences the outcome of enteric infections?

Answer 3

Type of organism

Infective load

Acute, chronic, or repeat infection

Host factors, eg: status of immune system, nutritional and general health status, and age

Significance is very different in developing world compared to developed world.

Question 4

How can enteric infections lead to death?

Answer 4

Can lead to diarrhoea which can lead to severe dehydration and if severe this can lead to death.

Question 5

How can enteric infections lead to malabsorption?

Answer 5

Can lead to diarrhoea which leads to malabsorption or can lead to malabsorption.

Question 6

What effects are seen in repeat infections of the GI tract?

Answer 6

Malnutrition

Growth stunting

Cognitive impairment (10IQ points per bout of diarrhoea on average)

Impaired immunity (+vaccine hyporesponsiveness)

Question 7

What is the world impact of diarrhoea?

Answer 7

2.2 million people die each year from diarrhoea related illness and 90% of these are children under 5 years of age.

Question 8

What is diarrhoea?

Answer 8

Increased water in stool causing an increase in stool frequency or passage of soft stools.

Passage of greater than 3 stools per day or a stool volume greater than 200mls

Regardless of definition generally the result is an increase in water in stool

Question 9

What drives water flux in the intestines?

Answer 9

Osmotic gradients caused by movement of osmotically active molecules:

Electrolytes

Sugars

Amino acids

Question 10

What drives secretion?

Answer 10

2 distinct processes establish an osmotic gradient which pulls water into the small intestinal lumen:

Digestion of food into small molecules of high osmolarity

Active secretion of electrolytes by crypt enterocytes

Question 11

How are electrolytes actively secreted by crypt enterocytes?

Answer 11

ATP is converted into cAMP by adenyl cyclase.

cAMP then activates Cl- channel which is pumped into the lumen. Cl- then pulls sodium into the lumen.

Question 12

How is water flux in the small intestine adjusted for absorption? What does this mean for medicating poor absorption caused by disease conditions?

Answer 12

Sodium dependent hexose transporter couples sodium and hexose transport.

Glucose is then transported to the basolateral side of the enterocyte via facilitated diffusion. Sodium is then pumped out to basolateral side creating high sodium concentration gradient which then causes water to diffuse towards basolateral membrane via osmosis.

Oral rehydration solutions use this information to rehydrate people when they are sick

Question 13

What are the mechanisms of diarrhoea production?

Answer 13

Increased active secretion of electrolytes and thus water

Damage to brush border resulting in malabsorption of nutrients and electrolytes

Damage to brush border, loss of disaccharidase activity, increased osmolality of stool

Altered motility, less time for water absorption.

In broader terms:

Inflammatory

Secretory

Osmotic

Motility related

Question 14

What is the type of diarrhoea dependent on?

Answer 14

Virulence factors expressed by the pathogen

Question 15

What are the types of virulence factors that can cause diarrhoea?

Answer 15

Virulence factors enabling adhesion

Virulence factors enabling invasion

Toxins: Enterotoxins, cytotoxins, neurotoxins

Question 16

What do enterotoxins do?

Answer 16

Interfere with salt and water transport by enterocytes, resulting in net loss of water. Enterocytes are not damaged.

Question 17

What do cytotoxins do?

Answer 17

Cause damage to cells of the intestine

Question 18

What do neurotoxins do?

Answer 18

Central or local nervous system stimulation causing increased intestinal motility.

Question 19

When are bacterial toxins produced?

Answer 19

Can be preformed in food or produced by bacteria after ingestion

Preformed toxin disease usually has short incubation period

Toxins may be heat labile or heat stable (destroyed or not destroyed by cooking)

Question 20

What does vibrio cholerae do?

Answer 20

It is a curved gram negative rod that produces a powerful enterotoxin which produces a profuse watery diarrhoea leading to severe dehydration and may cause death within hours in malnourished, debilitated hosts

Question 21

How does vibrio cholerae cause disease?

Answer 21

Vibrio are mostly killed by stomach acid, the ones that survive adhere to small intestinal enterocytes and produce cholera toxin.

Cholera toxin as 2 subunits; an A subunit and a B subunit.

A subunit enters the enterocyte and enhances adenyl cyclase activity resulting in overproduction of cAMP which opens Cl- channels resulting in water loss. This can be counteracted by oral rehydration solutions.

B subunit binds to specific receptors on enterocytes

Question 22

What kind of diarrhoea is caused by shigella?

Answer 22

Inflammatory diarrhoea (colitis)

Question 23

What species of shigella cause diarrhoea?

Answer 23

S. sonnei

S. dysenteriae

S. flexneri

S. boydii

Question 24

How does shigella cause disease?

Answer 24

Binds to M cells (lymphoid cells) in the large bowel lumen.

They force M cells to endocytose them

Shigella produces IpaA, IpaB, IpaC, IpaD antigens which allow entry of shigella into host cytoplasm

Host cell is then forced to reach out and engulf bacteria by Ipa proteins causing cell to form filopods

Bacteria are then enclosed within endocytic vacuoles

They are then released into submucosa where macrophages engulf them.

They then survive within macrophage. Macrophages then produce IL-1 which attracts PMNLs into the area

This results in inflammatory cells squeezing between cells.

Shigella then enter enterocyte again and genes on plasmids encode outer membrane proteins (icsA) which cause condensation of host cell actin behind the bacterial cell and this pushes bacterial cell from one cell to the next adjoining cell.

Cells are damaged by inflammatory process from cytotoxins such as shiga toxin. Inflammatory diarrhoea. Blood and pus = dysentery.

Question 25

What are the symptoms of shigella infection?

Answer 25

Prodromal upper intestinal watery diarrhoea

Frequently scanty dysenteric stools

Blood

Pus

Mucus

Tenesmus

Significant protein loss resulting in malnutrition and impaired immunity.

Question 26

Which bacteria produce neurotoxins?

Answer 26

S. aureus enterotoxin B

Clostridium botulinum

Bacillus cereus

Question 27

Which bacteria produce enterotoxins?

Answer 27

Vibrio cholerae

ETEC

Salmonella species

Campylobacter

Clostridium perfringens type A

Question 28

What bacteria produce cytotoxins?

Answer 28

Shigella

Salmonella

Campylobacter

Clostridium difficile toxin B

Question 29

What bacteria use mucosal invasion for diarrhoea production?

Answer 29

Shigella

Campylobacter

EIEC

Yersinia enterocolitica