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MB4030 > L8: V. cholerae & C. diff > Flashcards

L8: V. cholerae & C. diff Flashcards

1
Q

Cholera is a __ disease

A

water-borne

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2
Q

What percentage of cholera cases can be successfully treated with oral rehydration salts?

A

up to 80%

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3
Q

Which two serogroups of V. cholerae cause outbreaks?

A

O1 (majority) and O139

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4
Q

Features of V. cholerae

A
  • Gram negative
  • Motile, curved rod with a single polar flagellum
  • Produces a complex A-B toxin
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5
Q

How is V. cholerae transmitted?

A

via the oral route: consumption of contaminated water

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6
Q

How many serogroups are known?

A

200

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7
Q

2 subgroups of serogroup O1

A

Classical and El Tor

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8
Q

Symptoms of cholera

A

large amounts (loss of ~20L water/day) of diffuse watery diarrhoea (‘rice water stool’), vomiting, muscle cramps, circulatory collapse in serious cases

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9
Q

Survival of acute diarrheal disease (cholera) leads to…

A

recovery with immunity - some potential to carry and shed the pathogen

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10
Q

Features of O1 El Tor strain

A

haemolytic, polymyxin B resistant

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11
Q

First line treatment for cholera

A

Oral or intravenous hydration - prompt restoration of lost fluids and salts

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12
Q

What antibiotic is recommended as first line treatment for adults, in conjunction with hydration?

A

Doxycycline - inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit

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13
Q

What is required for successful colonisation of the gut by V. cholerae?

A

motility - to penetrate the mucus barrier to adhere to SI mucosal surface

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14
Q

V. cholerae preferentially colonises the __ __ __, forming microcolonies in __ __.

A

distal small intestine
villous crypts

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15
Q

How is the mucosal barrier disrupted?

A
  • Widening of intracellular spaces
  • Disruption of the apical junction
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16
Q

What type of toxin does V. cholerae produce?

A

Hexametric cholera enterotoxin, which is composed of 1A chain and 5B chains

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17
Q

Which part of the toxin is the toxic component?

A

The A chain (ADP-ribosylase)

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18
Q

Toxin binds to __ on the surface of intestinal epithelial cells.

A

GM1 ganglioside receptor

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19
Q

What immune cells are involved in disrupting the mucosal barrier in cholera infection?

A

Influx of neutrophils, macrophages, APCs & other lymphocytes into lamina propria. Cholera also triggers the production of innate effector molecules at the mucosal surface, such as lactoferrin, defensins & oxidases.

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20
Q

Which proteins generate ROS in cholera infection?

A

dual oxidase 2 (DUOX2), inducible nitric oxide synthase (iNOS)

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21
Q

Which signalling pathways are highly activated in response to cholera?

A

NLRP3 inflammasome and Type I IFN

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22
Q

Which cytokines are produced by APCs in cholera infection?

A

IL-1β (pro), IL-6 (pro/anti), IL-17 (pro)

23
Q

Protection against cholera infection is delivered by

A

V. cholerae specific IgA antibodies

24
Q

What is the primary virulence factor of V. cholerae?

A

Enterotoxin production

25
Q

What is a requirement of live attenuated (recombinant) vaccines?

A

No virulent forms present in inoculum

26
Q

Inactivated __ is not effective as a vaccine.

A

enterotoxin

27
Q

2 examples of vaccines for people travelling developed by PaxVax Corporation

A

PXVX0200 (Vaxchora): single-dose, oral, live attenuated vaccine against cholera
PXVX0103: oral, live adenoviral-based vaccine against Avian Influenza (H5N1)

28
Q

What strain in Vaxchora is well-tolerated and protects against cholera?

A

CVD 103-HgR

29
Q

Features of Clostridium difficile

A
  • Gram positive
  • Spore-forming
  • Anaerobic bacillus
30
Q

How is C. diff transmitted?

A

via the faecal-oral route

31
Q

How does C. diff cause infection?

A

by colonising the LI, when normal flora is reduced by antibiotics
- generally nosocomial

32
Q

Risk factors associated with CDI

A
  • higher risk after antimicrobial therapy
  • patients over 65 years
33
Q

CDI can affect any part of the colon but __ __ is most commonly affected.

A

distal segment

34
Q

Main protective barrier against CDI

A

normal intestinal microflora

35
Q

C. diff infection can result in…

A

pseudomembranous colitis (potentially fatal) or antibiotic-associated diarrhoea

36
Q

What play an important role in the induction of C. diff spore germination?

A

bile acids

37
Q

__ __ concentrations appear to be higher in faeces of patients with CDI.

A

primary bile (cholic acid)

38
Q

__ __ concentrations appear to be higher in faeces of healthy people.

A

secondary bile (deoxycholic acid)

39
Q

Is C. diff invasive?

A

No

40
Q

C. diff virulence is caused mainly by

A

enzymes such as collagenase and hyaluronidase, as well as toxins

41
Q

C. diff virulence leads to

A
  • damage in epithelial cell cytoskeleton
  • disruption of tight junctions → fluid secretion
  • neutrophil adhesion → local inflammation
    (leading to breakdown of gut barrier integrity, & loss of functionality)
42
Q

C. diff toxins

A

Toxin A (an entertoxin) and toxin B (a cytotoxin)

43
Q

What effect do C. diff toxins have?

A

They are transported to cell cytoplasm & activate the Rho family of GTPases
- inactivate G protein
- impair actin-polymerisation
- cytoskeletal disorganisation & loss of cell function

44
Q

~6% of C. diff strains produce a __ __.

A

binary toxin (an extra toxin)

45
Q

What feature does C. diff 027 strain have?

A

a frameshift stop codon in the tcdC negative regulator (hyper-expresses the A & B toxins)
027 strain has increased sporulation rate

46
Q

All C. diff 027 strain isolates are positive for what?

A

the binary toxin

47
Q

027 strain of C. diff is resistant to?

A

fluoroquinolones

48
Q

How is CDI diagnosed?

A

by detection of toxin in stools of patients by ELISA assays

49
Q

What is used in C. diff culturing?

A

cycloserine-cefoxitin fructose agar (CCFA)

50
Q

What antibiotics are recommended for C. diff treatment?

A

Vancomycin
Fidaxomicin

51
Q

Restrict specific antibiotics, especially __ and __, in elderly population for C. diff control.

A

Cephalosporins and Clindamycin

52
Q

Name 2 potential new therapies under trial for CDI

A
  • probiotics
  • FMT
53
Q

Human monoclonal antibody against the C. diff toxin B?

A

Bezlotoxumab (Zinplava)
- has been shown to reduce the risk of recurrent CDI in those at high risk of recurrence
- inhibits the binding of toxin B & prevents its effects on mammalian cells

MB4030 (10 decks)

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