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Microbiology & Immunolgy > Bacterial Pathogenesis II (Toxins) - L8 > Flashcards

Bacterial Pathogenesis II (Toxins) - L8 Flashcards

1
Q

Superantigens

A

proteins that produce a massive cellular immune response that can lead to fatal toxic shock

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2
Q

What to superantigens lead to?

A

a continuum of worsening inflammation:

systemic inflammatory response syndrome -> sepsis -> severe sepsis (sepsis+organ dysfunction) -> septic shock

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3
Q

Sepsis

A

documented, or suspected infection, with other criteria that would suggest an inflammatory response

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4
Q

Why is sepsis important?

A

very common, expensive, and a high mortality:

  • 750K cases: 52% in IC, 17% life support
  • 28% mortality overally
  • most common cause of death of IC patients (excluding coronary IC patients)
  • $14 billion in US
  • 25% fatality sever sepsis
  • 50% fatality septic shock
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5
Q

Sepsis causative agents

A

47% gram-pos, 62% gram-neg

gram-pos: staphylococcus aureus, MRSA, s. epidermidis, s. pneumoniae, GAS

gram-neg: pseudomonas sp., e. coli, klebsiella sp., acinetobacter sp, enterobacter

also fungi

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6
Q

sites of infection for sepsis

A
  • respiratory system
  • urogenital tract (female > male)
  • abdomen
  • medical device (catheters, ventilators)
  • wound/soft tissue
  • CNS
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7
Q

superantigen mechanism

A
  • DIRECT stimulation of T cells
  • bypasses antigen processing and presentation
  • bind MHC-II and variable portion of beat chain or T cell receptor
  • may also engage CD28, a costimulary molecule on T cells
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8
Q

What do SAgs activate?

A
  • far more T cells than normal pathway (20% vs
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9
Q

endotoxin lipid A

A

may also cause toxic shock, but through a pathway mediated by TLR4

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10
Q

GAS (group A streptococcus) key facts

A
  • wide ranging disease: impetigo, necrotizing fascilititis (flesh-eating bacteria, to toxic shock)
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11
Q

What are important virulence factors for GAS?

A

Superantigens, including:

  • SpeA
  • SpeC
  • exotoxin Z
  • streptococcal superantigen (SSA)

most are encoded within bacteriophage genomes

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12
Q

What is the generalized mechanism of ADP-ribosylating toxins?

A
  1. catalytic glutamate (Glu, E) residue of toxin forms hydrogen bond with NAD
  2. nucleophilic atack of NAD
  3. transfer of ADP ribose to substrate
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13
Q

What kind of targeting do ADP-ribosylating toxins have?

A
  • some very precise (diptheria toxin)

- some modify numerous (pertussis toxin, ExoS)

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14
Q

What kind of toxin are Cholera and Heat-Labile (LT) toxin?

A

ADP-ribosylating

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15
Q

What is the structure of cholera/LT toxins?

A

AB5 toxin pentamer of B bununits surrounding the catalytic A subunit “lunar landers”

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16
Q

Where are the cholera/LT toxins located?

A
  • cholera within prophage genome

- LT on virulence plasmid

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17
Q

How are cholera/LT secreted?

A

Type II systems, with additional outer membrane vesicles (OMV’s) for the LT

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18
Q

What do cholera/LT toxins target, and what is the result

A
  • target Gs, which regulated the activity of adenylate cyclase
  • results in the inhibitio of GTPase activity of Gs, massive overproduction of cAMP, dysregulation of chloride and other ion transporters, diarrheal disease
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19
Q

What are visible signs of cholera?

A

severe dehydration, decreased skin turgor which produces “washer woman’s hand”

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20
Q

How do CT and LT differ after secretion?

A
  • CT diffuses away from the bacterium after secretion
  • LT binds to LPS via a binding site on B subunits that the CT-B subunits lack, then is released from the pathogen as OMVs form
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21
Q

Where does diptheria toxin (DT) originate from?

A

Corynebacterium diptheriae, a gram-pos faculative anaerobe that causes respiratory and cutaneous diptheria

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22
Q

What is the structure of DT?

A

an AB toxin that is encoded by a single gene within a prophage;

in order A, T, B

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23
Q

How is DT secreted?

A

secreted as a single polypeptide via an amino terminal signal peptide (GSP), cleavage of signal peptide (signal peptidase)

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24
Q

What happens to DT after secretion?

A

DT is cleaved b host furin (a protease) into A and B fragments, but the disulfide bond between cys residues keeps proteolytic fragments covalently bound to each other

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25
Q

What does DT target, and what does that result in?

A
  • targets elongation factor-2 (EF-2)

- results in inhibition of protein synthesis

26
Q

How toxic is DT?

A

DT is EXTREMELY POTENT:

  • a single molecule is enough to kill a cell
  • lethal dose is ~100 ng/kg in humans
  • 1/3 most deadly toxins: diptheria, tetanus, botulism
27
Q

A detailed pathway of DT

A
  1. B domain recognizes the EGF-like growth factor (HB-EGF) in the plasma membrane
  2. receptor-meditated endocytosis
  3. low pH of the endosome induces T to begin producing pores, reduction of the disulfide bond, and escape of catalytic A fragment into the cytosol
  4. a fragment catalyzes the transfer of ADP-ribose from NAD to EF-2, which inhibits the function of EF-2 in protein synthesis
  5. ADP-ribosylation of EF-2 inhibits translation (EF-2 is needed for moving of tRN)
  6. no translation = cellular death
28
Q

Do all living cells require iron?

A

Yes

29
Q

Where is Fe++ in the human body?

A

it’s tightly sequestered by iron binding proteins (ferritn, etc), hemoglobin, and within enzymatic reaction centers

30
Q

What is the relationship between DT and iron?

A

in the absence of Fe++, the DT gene is expressed, and in its presence DT is repressed by DtxR;

the death of host cells makes Fe++ bioavailable to C. diptheriae

31
Q

Where does Exotoxin A originate from?

A

Pseudomonas aeruginosa, a gram-neg aerobe that causes mild skin, ear infections to severe pneumonia (in immune compromised, cystic fibrosis patients)

32
Q

What is the structure of exotoxin A?

A

an AB toxin with domains in the reverse order of DT, without proteolytic cleavage;

in order, B, T, A

33
Q

How is exotoxin A secreted?

A

as a single polypeptide via an amino terminal signal peptide (GSP)

34
Q

What happens to exotoxin A after it is secreted?

A

a signal peptidase cleaves signal peptide in periplasm type II secretion across the outer membrane

35
Q

What does exotoxin A target, and what does this result in?

A
  • targets EF-2

- this results in the inhibition of protein synthesis, which leads to cell death

36
Q

What is the overall pathway of exotoxin A?

A
  1. receptor meditated endocytosis (LDL receptor related protein 1)
  2. proteolytic cleavage
  3. retrograde traffic to endoplasmic reticulum
  4. translocation of A domain into cytoplasm
37
Q

What do bacteria producing shiga-like toxins commonly cause?

A

hemolytic uremic syndrome (HUS)

38
Q

What is hemolytic uremic syndrome (HUS)?

A

the most common cause of acute kidney failure in children; causes destruction of red blood cells and kidney failure;
Gb3 is present in greater amounts in renal epithelial tissues

39
Q

Where do shiga-toxins orignitate?

A

shigella dysenteriae, and some strains of E. coli (EHEC)

40
Q

What is the structure of a shiga-toxin?

A

an AB5 toxin, encoded by two genes on bicistronic mRNA (fat star)

41
Q

How is shiga-toxin secreted? (detailed)

A
  1. amino-terminal signal peptides, cleavage by ignal peptidase and assembly in periplasm
  2. Stx type 1 is retained in the periplasm and only released upon death of bacterium
  3. Stx2 may be released like Stx1, but could also have an alternative pathway across OM
42
Q

What does Stx target, and what does that result in?

A
  • A subunit is an N-glycosidase that enters the cytosol and cleaves off a single adenine residue from the 28S rRNA of the 60S ribosomal subunit;
    this ultimately inhibits protein synthesis
  • the B pentamer mediates holotoxin binding to the well-characterized glycolipid receptor Gb3
  • the overall result is inhibition of translation, which leads to cell death
43
Q

What is the detailed mechanism of Stx toxicity?

A
  1. A1:B5 toxin binds to Gb3 receptor
  2. binding mediated by subunits
  3. entire toxin-Gb3 complex is endocytosed
  4. retrograde transport to gogli then ER
  5. A1 fragment released into cytoplasm
  6. loop b/w A1 and A2 cleaved by trypsin and/or furin
  7. A1 fragment has N-glycosidase activity that depurinates a critical residue in the 28S rRNA of 60S ribosomes
44
Q

Which major toxin is a protease?

A

Tetanus toxin

45
Q

Where does tetanus toxin originate?

A

Clostridium tetani, a gram-pos, obligate anaerobe that causes tetanus: painful tightening, spams, rigidity of the muscles, lockjaw with a 10% fatality rate

46
Q

What is the structure of tetanus toxin?

A

a single gene, plasmid encoded that gets cleaved into two fragments linked by a disulfide bond

47
Q

What does tetanus toxin target?

A

it’s a neurotoxin, so the CNS

48
Q

What is the tetanus toxin pathway (detailed)?

A
  1. toxin binds peripheral nerve terminals
  2. gets internalized
  3. retrograde transport within axon to reach CNS
  4. delivered into intersynaptic space b/w motor neuron and inhibitory interneuron
  5. attaches to gangliosides at the presynaptic inhibitory motor nerve endings
  6. taken into axon by endocytosis
  7. proteolytic cleavage of synaptobrevin/VAMP prevents neuroexocytosis
  8. release of inhibitory neurotransmitters across synaptic cleft
49
Q

Which major toxin is a proteolytic toxin?

A

botulinum toxin

50
Q

Where does BoTox originate?

A

clostridium botulinum, a gram-pos obligate anaerobe; which causes botulism (aka flaccid paralysis)

51
Q

What is the structure of botox?

A

a single gene, may be located on the chromosome, a plasmid, or a bacteriophage cleaved into two fragments linked by a disulfide bond

52
Q

How is botox secreted?

A
  1. binds to presynaptic stimulatory terminals
  2. proteolytic cleavage of VMAP/synaptobrevin
  3. release of stimulating neurotransmitter (acetycholine) across synaptic cleft
53
Q

What does botox target, and what is the end result?

A
  1. it is a neurotoxin that targets peripheral neuromuscular synapses; permanently damages nerve endings
  2. also causes food poisoning; gets absorbed by the GI and passes into the blood stream to reach synapses
54
Q

What is heat-stable toxin (ST)?

A

a hormone (guanylin and urogunalyin) mimic

55
Q

How is ST secreted?

A

through a TolC system

56
Q

What is the largest class of bacterial toxins?

A

pore forming toxins (~30% of known toxins)

57
Q

What are pore forming toxins?

A

toxins that are secreted as soluble proteins, but still have the capability to form transmembrane channels (pores)

58
Q

What is a common pore forming toxin?

A

Staphylococcal a-toxin (a-hemolysin)

59
Q

where does staphylococcal a-toxin (a-hemolysin) originate?

A

from staphylicoccus aureus, a gram-pos facultative anaerobe, that causes impetigo, pneumonia, food poisoning, bacteremia, and toxic shock

60
Q

What is the structure of staphylococcal a-toxin (a-hemolysin)?

A

a single gene encoded on chromosome, expressed as a single polypeptide with N-term signal peptide for secretion via GSP

Microbiology & Immunolgy (8 decks)

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