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Bacterial Pathogenicity > L9. C. Diff Pathogenesis > Flashcards

L9. C. Diff Pathogenesis Flashcards

1
Q

What does C. diff stand for?

A

Clostridioides Difficile

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2
Q

What type of bacterium is Clostridioides difficile?

A

Gram positive, spore forming, anaerobic bacterium.

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3
Q

How does atmospheric oxygen affect Clostridioides difficile?

A

Atmospheric oxygen kills it immediately; it cannot survive in O2 at all.

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4
Q

When did Clostridioides difficile evolve?

A

It evolved before the great oxidation event, living in oxygen-deprived niches 2.5 billion years ago (pre-dates oxygen on the planet).

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5
Q

What spectrum of diseases does Clostridioides difficile cause?

A

It causes a spectrum of diseases collectively known as CDAD (C. diff associated diseases caused by CDI/ C. diff infection).

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6
Q

What are the characteristics of diarrhoea caused by C. diff infection?

A

> Self-limiting: Resolved within a few days.

> Recurring: In a small number of cases, it becomes frequent every few weeks, and the infection gets worse with each occurrence.

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7
Q

What are the immunological complications of C. diff infection?

A

> Two major immunological complications are:

  1. Pseudomembranous colitis
  2. Toxic megacolon
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8
Q

What are 3 symptoms and consequences of pseudomembranous colitis if left untreated?

A
  1. Yellow plaques, blisters filled with neutrophils infiltrate the tissue of large intestines causing Plaque build-up on colon surface.
  2. Colon wall completely compromised can lead to perforation, causing intestine contents to leak into the abdominal space, leading to sepsis.
  3. It is fatal if untreated and is rare but severe.
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9
Q

What are the symptoms and consequences of toxic megacolon and how is it treated?

A

> Rare but severe.

> Intestines can pop out of surgical wounds due to swelling.

> Surgery is the only treatment, which may involve removing the whole colon, requiring a colonoscopy bag.

> Patients often die in surgery.

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10
Q

What is the mortality rate of pseudomembranous colitis and toxic megacolon in the UK and globally?

A

These conditions are rare but responsible for 2000 deaths a year in the UK and probably hundreds of thousands around the world.

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11
Q

What is the leading cause of hospital-acquired infection worldwide?

A

Clostridioides difficile (C. difficile).

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12
Q

Which populations are most commonly affected by C. difficile infections?

A

Most commonly seen in the elderly, but increasingly seen in the community and younger populations (including children and pregnant women).

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13
Q

Can C. difficile infect animals? If so, which ones?

A

Yes, C. difficile can also infect animals such as pigs, cattle, horses, and chickens.

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14
Q

What are the associated healthcare costs of C. difficile in the United States and Europe?

A

> United States: $3.2 billion per year.

> Europe: €3 billion per year.

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15
Q

Why do C. difficile infections increase healthcare costs?

A

Due to extra time spent in the hospital, extending stays by around 10 days, and rooms being out of action for hours to days to stop transmission.

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16
Q

What is an issue with current C. diff data?

A

There is no current data in the UK, and EU data is needed.

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17
Q

Describe the disease progression of C. diff in 6 steps

A
  1. Patient receives antibiotic(s)
    >Antibiotic associated diarrhoea
    >95% of patients have antibiotics 2 weeks before symptoms
  2. Alterations in normal gut flora
    >Antibiotic induced dysbiosis allows C. diff to colonise the niche and grow.
  3. Infection with C. difficile spores
    >Resistant spore form (metabolically inactive), as is an anaerobe needs a spore to survive in environment, spreads to other people and starts growing.
  4. Spores germinate in gut forming vegetative cells
  5. Cells multiply, produce toxins and sporulate. Spores excreted
    >Toxins: TcdA and TcdB which cause symptoms.
  6. Causes more infections with spores from diarrhoea.
    >Spores are almost impossible to kill.
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18
Q

How long does the germination process take in C. diff?

A

90 mins

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19
Q

Describe evidence that the microbiota plays a role in C. diff infection

A

Microbiota bounces back within 2 weeks in mice and as this happens then C. diff is removed; this is probably what happens in humans.

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20
Q

When was Clostridioides difficile first isolated and under what name?

A

1935, isolated from the human infant gut as Bacillus difficile.

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21
Q

What is a notable characteristic of C. diff colonization in young babies and animals?

A

Most young babies are colonized with C. diff asymptomatically, producing toxins without causing diarrhea, a pattern also found in young animals.

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22
Q

When was C. difficile established as a major cause of antibiotic-associated diarrhea and pseudomembranous colitis?

A

1978.

23
Q

What other bacteria can cause diarrhea after antibiotics, though pseudomembranous colitis is mainly caused by C. diff?

A

P. colitis.

24
Q

How was C. difficile recognized between 1980 and 2000, and what are its major virulence factors?

A

It was recognized as a gut commensal bacterium in about 5% of healthy adults. Toxins A and B were characterized as major virulence factors.

25
Q

What limitation in screening was noted between 1980 and 2000 for C. difficile?

A

There was no genetic screening available at that time.

26
Q

What happened in 2003 regarding C. difficile in Quebec and Philadelphia

A

Epidemics occurred due to new fluoroquinolone-resistant “hypervirulent strains” (NAP1/027).

27
Q

What happened in 2008 regarding C. difficile strains in hospitals, and what was their origin?

A

Other hypervirulent strains (078) appeared in hospitals, previously associated with animal infections, indicating a zoonotic spillover.

28
Q

What was the major change in the classification of C. difficile in 2016?

A

It was renamed Clostridioides difficile to reflect the new understanding of genomic variation in the wider Clostridia family, with Clostridia being re-characterized into different genera.

29
Q

What were the trends and significant events in C. difficile-related deaths in England and Wales from 2001 to 2012?

A
  1. Initial undercount due to lack of screening.
  2. Deaths decreased to around 2000 by 2012 and remained stable with a slight increase.
  3. 2007 saw an outbreak from hypervirulent strains from America, with a decline due to NHS measures (Ribotype 037/ NAP1)
  4. Deaths and infections continue to grow significantly in countries with less funded healthcare systems, a major issue in the US.
30
Q

What was the dominant infection strain of C. difficile in the UK in 2001, and how did it change by 2011?

A
  1. 2001: 001 strain dominant.
  2. 2004-2005: Outbreak of new 027 (NAP1) strain.
  3. By 2007: Over half of UK infections caused by 027 strain, 001 strain down to 8.7%.
  4. By 2011: NHS efforts reduced 027 cases to 12.4%.
31
Q

What is the current status of the 027 strains of C. difficile in England, and what has changed?

A

The 027 strains are under control, but there is now a massive variation of C. diff strains. The strains labeled “others” indicate a wide collection of random C. diff strains, suggesting little evidence of hospital transmission.

32
Q

What does the presence of many different C. diff strains in hospitals indicate?

A

It indicates that the infections are coming from a separate reservoir, not from hospital transmission, as hospital transmission would show lots of patients with the same strains.

33
Q

What does a decrease in same-strain infections in hospitals suggest?

A

It suggests that hospital cleaning efforts are working.

34
Q

Despite hospital cleaning efforts, what remains a problem with C. diff infections?

A

There is a baseline number of infections occurring from outside of the hospital.

35
Q

What is the strain responsible for the North American outbreaks, and what is its name in Europe?

A

The strain is NAP1 (North American Pulse-field electrophoresis Type 1), known in Europe as Ribotype 027.

36
Q

What is a notable characteristic of the Ribotype 027 strain

A

It is fluoroquinolone-resistant.

37
Q

What are 4 key characteristics of the “hyper-virulent” 027/NAP1 (ribotype 027) strains of C. difficile?

A
  1. Previously rare.
  2. Now fluoroquinolone-resistant (suggests recent acquisition).
  3. Associated with large outbreaks (more transmissible).
  4. Associated with more severe disease (hyper-virulent), becoming more harmful.
38
Q

What are the 4 specific characteristics of the 027/NAP1 (ribotype 027) strains?

A
  1. Produces more spores, making it more transmissible.
  2. Produces more toxin in vitro, leading to more severe disease.
  3. Produces a third toxin – binary toxin (CDT).
  4. Contains an 18 bp deletion in tcdC, which upregulates toxin production.
39
Q

What bias is noted in the collection of C. difficile strains?

A

Places not collected have bigger threats than C. diff, so they aren’t being worried about as much, but 027 strains are found everywhere and have gone global.

40
Q

What is trehalose sugar, and why is it significant in relation to C. difficile?

A

Trehalose sugar is mainly a manufactured sugar used to make ice cream smoother and has become cheaper in the past 20 years due to enzymatic production from plant starch. C. diff, particularly the 027 lineage, is very good at metabolizing trehalose.

41
Q

What mutation in epidemic ribotype 027 increases its virulence?

A

A point mutation in treR, a regulator of sensing trehalose, switches the enzymatic pathway for degrading it and using it as a carbon source. This mutation makes the strain 500 times more sensitive to trehalose and using it as a carbon source.

42
Q

What happens when the treA gene (trehalose degradation enzyme) is deleted in ribotype 027 in mice?

A

The virulence is massively attenuated, but supplementation with trehalose enhances virulence, showing that trehalose in food causes increased virulence.

43
Q

When do most C. difficile infections occur?

A

Most C. difficile infections follow treatment with antibiotics.

44
Q

Why does an intact microbiota prevent colonization/infection with C. difficile?

A

> Microbiota are natural occupiers and don’t want to give up their niche, so they compete with most pathogens infecting the colon as microbiota are evolved to live there.

  1. They effect bile acid metabolisation, and therefore mediate sporulation and germination of C. diff (bile salts = germinant for C. diff)
  2. They outcompete pathogens by consuming available food.
  3. They produce metabolites which C. diff doesn’t like, such as SCF.
  4. Bacteria directly produce bacteriocins which kill C. diff (antibacterial).
  5. Microbiota modulate the host innate immune response, producing antimicrobial peptides to which C. diff is sensitive.
45
Q

What is a prerequisite for C. diff infection (CDI)?

A

Dysbiosis (an imbalance in the gut microbiota) is a prerequisite for CDI (C. Diff Infection)

46
Q

How does the microbiota recover after a C. diff infection is cleared?

A

The microbiota recovers naturally as the infection is cleared.

47
Q

How can the recovery of microbiota be exploited to treat C. diff infection and what is evidence for this?

A

Faecal microbiota transplantation from a healthy donor is 90% effective for treating C. diff infection.

48
Q

Which animal model was previously used for C. difficile infection but is now barely used?

A

Golden Syrian Hamsters.

49
Q

Which animal model is mostly used now for C. difficile infection studies?

A

C57BL/6 Mice (standard lab mouse).

50
Q

Describe the hamster model for studying C. difficile infection, what is was used to study specifically and why it was stopped being used.

A

> Clindamycin-treated hamsters are challenged with C. difficile spores.

> C. difficile infection is lethal within a few days, unlike in humans.

> Used to study the acute phase of C. difficile infection where toxins are key virulence determinants.

> Model went out of use due to ethical concerns (animals died), inaccuracy (humans don’t die in 3 days after infection), and hamsters not being commonly used species in biology.

51
Q

What are the advantages of using the mouse model (C57BL/6 Mice) for C. difficile infection studies?

A
  1. Cheaper as mice can be caged together (social, unlike aggressive hamsters).
  2. Availability of reagents and knock-out animals for mice.
  3. Less lethal for mice (C. diff infection).
51
Q

What are 3 reasons to why the hamster model no longer commonly used for C. difficile infection studies?

A
  1. Ethical concerns as animals died.
  2. Doesn’t replicate what happens in humans accurately (humans don’t die in 3 days after infection).
  3. Hamsters are not commonly used species in biology, unlike mice which have many monoclonal antibodies and other important reagents for use in the lab
52
Q

What are the advantages of using the mouse model (C57BL/6 Mice) for C. difficile infection studies?

A
  1. Cheaper as mice can be caged together (social, unlike aggressive hamsters).
  2. Availability of reagents and knock-out animals for mice.

3.Less lethal for mice (C. diff infection)

53
Q

Describe how the mouse model is used for studying C. difficile colonization and what it is specifically used to study.

A

> Clindamycin-treated mice are challenged (become susceptible to infection) with C. difficile spores.

> By giving a cocktail of antibiotics instead, it makes C. diff infection more severe and can be tailored to mimic different human infections.

> High number of spores are shed in the feces, referred to as a super-shedder state.

> After cessation (microbiota recovers) of antibiotic treatment, the number of C. difficile spores in the feces decreases, but a subsequent dose of clindamycin returns animals to the super-shedder state.

> This model is a good replication of relapsing C. diff in humans.

Bacterial Pathogenicity (11 decks)

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