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Flashcards in M32: Exotoxins Deck (21)
1

1. What are toxins?

Molecules that have the capacity to _ or _ when administered in (large / small) quantities.

2. Who makes toxins?

many _, some _ and _ (rotavirus?)

3. The two major types of bacterial toxins include:

Endotoxin: part of Gram-(positive / negative) bacterial cell (_ or _), very heat-(stable / labile)

Exotoxin: _, usually heat-(stable / labile)

injure or kill
small

bacteria
fungi and parasites

negative
LPS or LOS
stable

secreted
labile

2

4. Characteristics of bacterial exotoxins include:

a. Most are _
b. Active in (greater / smaller) amounts than endotoxin
c. One bacterial cell can make (1 / >1) toxin
d. Gram-positive bacteria are generally (better / worse) toxin producers, but there are some (good / poor) toxin-producing Gram-negatives

5. Nomenclature:

a. _: fungal toxin
b. _: affects nervous system
c. _: affects GI system
d. _: lyses RBCs

6. Exotoxins can be good _ targets.

a. proteins
b. smaller
c. >1
d. better
good

a. Mycotoxin
b. Neurotoxin
c. Enterotoxin
d. Hemolysin

6. vaccine

3

Enterotoxins:

1. Examples of enterotoxin producers:

a. _ (makes emetic and diarrheal enterotoxins)
b. _
c. _ (toxins A and B).
d. _: heat-labile and heat stable enterotoxins, Shiga toxin
e. Some _ isolates: Shiga toxin
f. _
g. _

2. What are the effects of enterotoxins?

a. Mainly _ effects such as _ and _ (some also cause _).

a. Bacillus cereus
b. Staphylococcus aureus
c. Clostridium difficile
d. E. coli
e. Shigella
f. Clostridium perfringens
g. Vibrio cholerae

a. GI
diarrhea and abdominal cramps
vomiting

4

Enterotoxins:

3. Enterotoxin actions can include:

a. Altering intestinal _ levels (e.g., cholera toxin, LT of ETEC increase cAMP; ST of ETEC increases cGMP)

b. _ cells (e.g. Shiga toxin)

c. Acting as _ to induce an _ response (e.g. S. aureus enterotoxins)

d. Affecting _ permeability by inducing _ changes (e.g. C. difficile toxins)

4. What is the importance of enterotoxin-producing for human disease?

a. These bacteria are responsible for many _ diseases.

b. In the USA, these bacteria cause mostly _ but in developing countries are an important cause of _.

c. _ are most at risk.

d. These bacteria are usually transmitted via the _.

e. Treatment varies according to disease, but always involves _.

a. cyclic nucleotide

b. Killing

c. superantigens
inflammatory

d. tight junction
signal transduction

a. diarrheal

b. morbidity
death

c. Children

d. fecal-oral route

e. restoration of fluid/electrolyte balances

5

Neurotoxins:

1. Bacterial neurotoxins are the most _ toxins known! For example, these are ~100,000 times more _ than sarin gas.

2. The two most important bacteria producing neurotoxins are _ and _.

3. Tetanus is a (flaccid / spastic) paralysis, while botulism is a (flaccid / spastic) paralysis.

4. Molecular Action of botulinum and tetanus toxins involve highly specific _ activity.

These toxins cleave neuronal proteins involved in _. This prevents synaptic vesicle docking and inhibition of _

5. Botulinum toxins are now used clinically to treat a wide variety of conditions such as
_, as well as for _ purposes.

1. potent
lethal

2. Clostridium botulinum
Clostridium tetani

3. spastic
flaccid

4. proteolytic

synaptic vesicle docking
neurotransmitter release

5. inappropriate muscle contractions
cosmetic

6

What are the differences in action between tetanus and botulinum neurotoxins?

a. Tetanus toxin:

i) Works on _ in _ (travels up motor neuron into the _).
ii) Blocks release of _ (e.g., glycine).
iii) Results in _.
iv) Motor neuron constantly excites _.
v) Result is _!

b. Botulinum toxin:

i) Acts at _
ii) Blocks release of _ (excitatory neurotransmitter)
iii) Without acetylcholine, muscles do not _.
iv) Result is _.

i) CNS in spinal cord, CNS
ii) inhibitory neurotransmitters
iii) constant stimulation of the motor neuron
iv) muscle
v) spastic paralysis

i) neuromuscular junction
ii) acetylcholine
iii) contract
iv) Flaccid Paralysis

7

Case Study: A 42 year-old oil company executive visits operations on the North Slope of Alaska. While there, he is invited to a Native American/Eskimo dinner prepared by workers. At the dinner he enjoys traditional foods, including home-prepared smoked fish. The next day he develops "double vision" (diplopia) and swallowing problems. He is admitted to a nearby clinic. He shows a normal leukocyte count. Urinalysis and chest x-ray appear normal. That day, three other people who also attended the dinner are also admitted with similar symptoms.

The disease progresses to a descending paralysis. Thirty-two hours after admission, the patient suffers a cardiopulmonary arrest but is resuscitated. Despite repeated efforts, spontaneous respiration cannot be maintained and he is placed on a mechanical respirator. He dies the next day.

Cause: _

Clostridium botulinum

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Clostridium botulinum:

2. Biology of Clostridium botulinum

a. Organism is a Gram-(positive / negative) (aerobic / anaerobic), (spore-forming / non-spore-forming) _.

Eight types (A-G) have been recognized on basis of the botulinum toxin serotype they produce. New type H just discovered in 2013.

3. Reservoirs and Transmission:

a. C. botulinum is found in _ throughout the world.

b. In the USA, _ is associated with home-prepared foods, particularly common in Alaska.

4. Virulence factors:

a. Botulinum toxin (all 9 serotypes cause similar symptoms except type _ also often causes vomiting). Type _ toxin causes most serious illness because it _.

b. Botulinum toxins are class _ select agents.

c. Spores: the ability to form spores gives _ to the organism. However, the toxin is _.

a. positive
anaerobic
spore-forming
rod

a. soil

b. Foodborne botulism

a. E
A
persists longer inside the neuron

b. A

c. heat-resistance
heat-sensitive

9

Clostridium botulinum:
Entry:

a. Classical foodborne botulism: acquired by _. This is often an _ (i.e., viable bacteria (need / don't need) to be present in the body to become ill)

b. Infant botulism: now most common form of botulism in USA. Newborns _ is colonized by C. botulinum and the toxin is then _ (i.e., this is an infection).

c. Adult infant botulism: _ of adult is colonized by C. botulinum after _ have disrupted normal flora. In vivo _.

d. Wound botulism: _ produced by C. botulinum growing in _. In vivo _.

e. Class A select agent: _ / _.

a. ingestion of contaminated foods
intoxication
don't need

b. GI tract
made in vivo

c. GI tract
antibiotics
toxin production

d. botulinum toxin
wound
toxin production

e. bioterrorism / biowarfare

10

Clostridium botulinum:

a. Symptoms: _, _ difficulties, followed by descending _, _ problems and other difficulties. Often infants with infant botulism first present with _.

b. All symptoms due to _. Naturally has a high _ rate.

c. Relatively (common / rare) in USA.

double vision
swallowing
flaccid paralysis
breathing
constipation

botulinum toxin
fatality

rare

11

Clostridium botulinum:

Treatment

i) _ antitoxin
ii) _ therapy
iii) With proper therapy, fatality rate can be (raised / lowered)
iv) If recovery occurs (can be a slow process), there are usually no long-term _.

Prevention:

i) Often follows ingestion of _. Prepare these foods carefully.
ii) Don't feed infants _.
iii) Heating at 80°C for 30 min (or ~5 min of boiling) will inactivate this _.
iv) Vaccine?

i) Botulinum
ii) Supportive
iii) lowered
iv) sequelae

i) home-prepared (smoked or canned) foods
ii) honey
iii) heat-labile neurotoxin
iv) A vaccine is available for special use.

12

Membrane active toxins ("hemolysins"):

1. What bacteria produce hemolysins:

a. Most Gram-(positive / negative) pathogens produce a _-dependent _, e.g., Streptolysin O, Listerolysin O

b. _ makes a toxin

c. Uropathogenic _ often make a hemolysin.

d. C. perfringens a toxin is a _ that may also activate endogenous _

e. Many others

2. Many "hemolysins" affect _ as well as _.

3. Most hemolysins disrupt _ function, either by forming _ (e.g., S. aureus a toxin) or by _ action (e.g., C. perfringens a toxin).

a. positive
cholesterol
cytolysin

b. Staphylococcus aureus

c. E. coli

d. lecithinase
phospholipases

2. WBCs
RBCs

3. membrane
pores
enzymatic

13

Toxins that Inhibit Mammalian Protein Synthesis:

1. Toxins catalyzing an _ of Elongation Factor _:

EF-2 + NAD -> ADPR-EF2 + nicotinamide

a. _ exotoxin A

b. _ toxin

c. Result is EF-2 is (functional / nonfunctional), so protein synthesis _ and mammalian cells _.

2. Toxins that block protein synthesis by inactivating _.

a. _ toxin (made by EHEC and some Shigella) removes one base from one _ subunit; the _ no longer functions and protein synthesis _.

1. ADP-ribosylation
2

a. Pseudomonas

b. Diphtheria

c. nonfunctional
shuts down
die

2. ribosomes

a. Shiga
rRNA
ribosome
stops

14

Case study: An 18 year old female is involved in a serious automobile accident where she suffers serious burns on extensive regions of her body. A few days after she is admitted to the hospital, the attending physician notices a greenish discoloration on the burn dressing. Within a few hours she develops a high fever (40°C) and chills. Her blood pressure drops and she has a high WBC count. Microscopy and blood cultures identify a Gram-negative rod that is an obligate aerobe. The patient is started on ampicillin and later switched to ceftriaxone but does not respond. She soon dies from sepsis.

Cause: _

Pseudomonas aeruginosa

15

Pseudomonas aeruginosa:

Characteristics

- Gram-(positive / negative), (aerobic / anaerobic), (motile / non-motile) _.

- Often make _ pigments (fluorescein and pyocyanin).
- Grow (slowly / rapidly).
- Highly _ resistant.
- Very hardy.
- Oxidase-(positive / negative).
- Opportunistic?
- Primarily an (intracellular / extracellular) pathogen.

Virulence Factors

a. _: causes necrosis

b. _ (_, _): cause tissue damage.

c. _: inhibits/kills WBCs

d. _: hemolysin, affects WBCs

e. _: promotes shock, relatively weak compared to others.

f. _ (_ / _): antiphagocytic, important for making biofilms that contribute to cystic fibrosis, can interfere with antibiotic action.

g. _: adhesion

negative
aerobic
motile
rod

blue-green
rapidly
antibiotic
positive
yes
extracellular

a. Exotoxin A

b. Enzymes (proteases, elastase)

c. Leucocidin

d. Phospholipase C

e. Endotoxin

f. Capsule (slime layer / biofilms)

g. Pili

16

Pseudomonas aeruginosa:

Transmission and reservoirs:

a. P. aeruginosa is _ in the environment

b. This bacterium usually can't penetrate the _, so it mainly causes diseases through (3). _ factors (e.g., use of catheters) also assist entry. Host defenses important (e.g., _ infections).

Disease

a. _ pathogen:

b. In healthy people, _ can resist disease.

c. Septicemic infections often involve _.

d. Diseases often with high _ rates.

e. Particularly important for _ infections, _ infections and patients with _ (UTIs) and _.

a. ubiquitous

b. epithelium
wounds, surgical incisions, burns
Nosocomial
cystic fibrosis

a. Opportunisic

b. WBCs

c. shock

d. mortality

e. cystic fibrosis
burn
catheters
iv lines

17

Pseudomonas aeruginosa:

Prevention

i) _: keep wound clean. In hospitals, keep patient's room clean; keep iv. lines and catheters _.

ii) Vaccine?

iii) Use _ agents (such as _) on wounds to prevent infection.

Treatment

i) Supportive therapy for _.

ii) P. aeruginosa (very / not very) antibiotic resistant.

iii) Should use _ specifically effective against this pathogen.

i) Sanitation/hygiene
to a minimum

ii) No vaccine available.

iii) topical
silvadene

i) shock

ii) very

iii) antibiotics

18

Drugs with some activity against Pseudomonas aeruginosa:

• _, _
• _, _ (not other 3rd generation cephalosporins)
• _, _, _ (not Ertapenem)
• _
• _, _, _
• _, _
• _ (colistin)

Caveats:

• There is significant _ of P. aeruginosa even to these agents.
• 50% of UPMC strains are resistant to _ or _
• 20% of UPMC strains are resistant to other "_" drugs
• May need to use _ of antibiotics for serious infections.

• Piperacillin, Ticarcillin
• Cefepime, Ceftazidime (not other 3rd generation cephalosporins)
• Imipenem, Meropenem, Doripenem (not Ertapenem)
• Aztreonam
• Gentamicin, Amikacin, Tobramycin
• Ciprofloxacin, Levofloxacin
• Polymyxins (colistin)

• resistance
• quinolones or aztreonam
• "antipseudomonal"
• combinations

19

Superantigens:

1. Examples include _, _, and _ (involved in scarlet fever).

2. Provide a way for Gram-(positives / negatives) to induce shock, fever, etc.

3. Lead to massive production of _, such as _ and _, that cause systemic effects such as shock.

1. toxic shock syndrome toxin, staphylococcal enterotoxin and streptococcal erythrogenic toxins

2. positives

3. cytokines
TNF and IL-1

20

Conventional antigen:

1) (Small subset of T cells respond / Massive T cell response)

2) (Desirable release of cytokines like IL-2 / Excess release of IL-2, et.c)

3) (Strong release of TNF and other proinflammatory cytokines / T cell : B cell interactions)

4) (Shock, fever / Antibody formation)

1) Small subset of T cells respond

2) Desirable release of cytokines like IL-2

3) T cell : B cell interactions

4) Antibody formation

21

Superantigen:

1) (Small subset of T cells respond / Massive T cell response)

2) (Desirable release of cytokines like IL-2 / Excess release of IL-2, etc.)

3) (Strong release of TNF and other proinflammatory cytokines / T cell : B cell interactions)

4) (Shock, fever / Antibody formation)

1) Massive T cell response

2) Excess release of IL-2, etc.

3) Strong release of TNF and other proinflammatory cytokines

4) Shock, fever