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MICB 308 > Toxins: CT, PT, TcdA/B, CdtAB > Flashcards

Toxins: CT, PT, TcdA/B, CdtAB Flashcards

1
Q

what are examples of toxins that alter signal transduction (2)

A
  • cholera toxin
  • pertussis toxin
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2
Q

what is one way that toxins can alter signal transduction

A
  • toxins can target or alter cAMP production
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3
Q

what bacteria produces cholera toxin

A
  • vibrio cholerae
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4
Q

what are the symptoms of cholera toxin (2)

A
  • produce watery diarrhea
  • lots of fluid secretion
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5
Q

cholera toxin structure (3)

A
  • AB5 toxin
  • one A
  • five identical B subunits that form a pentamer
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6
Q

cholera toxin: B subunits

A
  • binds to GM1 gangliosides
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7
Q

what is the cholera toxin’s mechanism of intoxication (7)

A
  1. B pentamer binds to receptor on host
  2. toxin is taken into endosome
  3. endosome fuses to Golgi
  4. retrograde transport of toxin from Golgi to the ER
  5. A subunit dissociates from pentamer
  6. A subunit enter the cytosol
  7. the A subunit ADP-ribosylates a heterotrimeric G protein
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8
Q

cholera toxin: how does the A subunit dissociate from the B subunit pentameter

A
  • disulfide bonds which holds the toxin together are reduced
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9
Q

cholera toxin: how does the A subunit enter the cytosol

A
  • enters via the Sec translocase
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10
Q

G proteins

A
  • large family of proteins that control variety of cell functions through signal transduction
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11
Q

G proteins: function (2)

A
  • bind GTP
  • hydrolyze GTP to GDP
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12
Q

G protein subunits

A
  • α, β, γ
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13
Q

G protein: α subunit

A
  • binds GTP
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14
Q

G protein: Gαs (3)

A
  • the “stimulatory” subunit
  • activates adenylate cyclase
  • increasing the production of cAMP
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15
Q

G protein: Gαi (2)

A
  • the “inhibitory” subunit
  • leads to decreased levels of cAMP in the cell
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16
Q

GTPase activity

A
  • converts GTP –> GDP
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17
Q

G protein: stimulatory signal pathway (8)

A
  1. ligand interacts with its receptor
  2. heterotrimeric G protein recruited to the receptor
  3. dissociated of subunits from the receptor and each other
  4. Gαs binds GTP and activated adenylate cyclase, increased cAMP levels
  5. Gαs has GTPase activity
  6. leads to lower cAMP levels
  7. re-association of the subunits and GDP is lost
  8. cycle continues
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18
Q

G protein: inhibitory signal pathway (8)

A
  1. ligand interacts with receptor
  2. recruitment of heterotrimeric G protein to receptor
  3. dissociation of subunits from receptor and each other
  4. Gαi binds GTP and inhibits adenylate cyclase, reducing cAMP levels
  5. Gαi has GTPase activity
  6. leads to higher cAMP levels
  7. reassociation of the subunits and GDP is lost
  8. cycle continues
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19
Q

cholera toxin mechanism of intoxication (4)

A
  • cholera toxin A subunit ADP-ribosylates Gαs
  • causes continuous dissociation of the G protein heterotrimer
  • leads to increased levels of cAMP
  • cell is permanently “ON” excessively produces cAMP
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20
Q

CFTR (2)

A
  • cystic fibrosis transmembrane conductance regulator
  • a channel that plays a key role in cystic fibrosis
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21
Q

what is the result of the cholera toxin intoxication (4)

A
  • phosphorylation of many proteins including CFTR
  • stimulation of secretion of chloride ions from crypt cells in intestine
  • inhibition of uptake of sodium and chloride ions from villous cells (intestine)
  • stimulates cells to secrete fluids, leading to watery diarrhea
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22
Q

pertussis infection: method of transmission (2)

A
  • aerosol infection
  • transmission achieved by coughing
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23
Q

how does pertussis establish infection (2)

A
  • bacterium binds mucin and ciliated epithelial cells that line trachea and nasopharynx
  • bacteria replicate and colonize
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24
Q

how does pertussis maintain infection (2)

A
  • evasion of the immune system
  • production of several toxins
25
Q

pertussis toxin: effects (2)

A
  • chemokine suppression
  • suppression of the recruitment of immune cells
26
Q

what bacterium produced pertussis toxin

A
  • bordetella pertussis
27
Q

pertussis toxin: structure (4)

A
  • AB5 toxin
  • one A subunit
  • four different B subunits
  • subunits linked by disulfide bonds
28
Q

pertussis toxin: A subunit

A
  • S1
29
Q

pertussis toxin: B subunit (4)

A
  • S2
  • S3
  • 2xS4
  • S5
30
Q

how does the pertussis toxin bind to the host cells

A
  • S2 and S3 bind to sialylated glycoproteins
31
Q

pertussis toxin: mechanism of intoxication (7)

A
  1. pertussis toxin binds to host cell
  2. retrograde transport from endosome, to Golgi, to ER
  3. S1 gets translocated to cytosol
  4. S1 ADP-ribosylates Gαi part of Gαi-GDP-β-γ
  5. Gαi-GDP-β-γ cannot re-associate with receptor and GDP does not get released
  6. Gαi is inactivated
  7. adenylate cyclase activity cannot be turned off, resulting in increased cAMP levels
32
Q

what are the consequences of the pertussis toxin intoxication (2)

A
  • inhibition of chemotaxis of alveolar macrophages (AM), monocytes, NK cells, and neutrophils to site of infection
  • an immune evasion mechanism
33
Q

Clostridium difficile

A
  • gram positive spore-former
34
Q

how common is C. difficile (2)

A
  • 5-10% of the population is naturally colonized as part of our microbiota
  • 25% can be colonized in hospital setting
35
Q

how does C. difficile behave after antibiotic treatment (2)

A
  • germinates in the gut
  • produces toxin once it germinates
36
Q

what do C. difficile toxins do (3)

A
  • damage mucosal cells in colon
  • produce accumulation of dead cells, mucin, and fibrin
  • produce pseudomembrane colitis
37
Q

psuedomembrane colitis (2)

A
  • when dead cells, mucin, and fibrin coalesce to form patchy lesions throughout the colon
  • extremely painful
38
Q

C. difficile: what toxins cause damage (2)

A
  • TcdA and TcdB cause the most damage
  • CdtAB causes damage to a lesser amount
39
Q

how can patients acquire C. difficile infection (2)

A
  • hospitalization
  • antibiotics that wipe out natural microbiota
40
Q

C. difficile: TcdA (3)
- structure
- target cell
- receptor

A
  • single protein with multiple domains
  • targets intestinal cells
  • glycoprotein GP96 located on the apical side of colonic cells
41
Q

C. difficile: TcdB target (3)
- structure
- target cell
- receptor

A
  • single protein smaller than TcdA
  • cells other than intestinal cells
  • CSPG4 and FZD on basolateral side of cells
42
Q

what are the components of TcdA toxin: A subunit

A
  • active site
43
Q

what are the components of TcdA toxin: B subunit (3)

A
  • cleavage site
  • translocation domain
  • receptor binding domain
44
Q

C. difficile: TcdA mechanism of intoxication

A
  1. entire protein endocytosed
  2. when pH changes, conformational change occurs in translocation domain
  3. “A” domain is translocated through the pore
  4. “A” is cleaved and released into cytosol
  5. A monoglucosylates small GTP-binding proteins
  6. G protein network is disrupted
  7. actin filaments depolymerize/breakdown
  8. tight junctions are destroyed, leading to diarrhea
  9. toxins also trigger apoptosis and pseudomembrane production
45
Q

C. difficile: TcdA cleavage of A subunit (2)
- mechanism
- activated by…

A
  • autoproteolysis
  • activated by lnsP6
46
Q

C. difficile: what small GTP-binding proteins does A subunit of TcdA affect (4)

A
  • Rho
  • Rac
  • CDC42
47
Q

C. difficile: how does A subunit of TcdA target the small GTP-binding proteins

A
  • monoglucosyaltes on threonine-37 residue
48
Q

apoptosis

A
  • programmed cell death
49
Q

heat-shock proteins (HSP)

A
  • proteins active under stress to fold proteins
50
Q

C. difficile: CdtAB structure (2)

A
  • A subunit: CdtA
  • B subunit: CdtB
51
Q

C. difficile: what is the receptor for the CdtAB’s B subunit

A
  • LSR
52
Q

C. difficile: CdtAB mechanism of intoxication; adherence/invasion (4)

A
  1. CdtB cleaves by cellular protease
  2. CdtB oligomerizes and binds to its receptor
  3. CdtA now binds to oligomerized CdtB
  4. entire complex is taken up into cell
53
Q

C. difficile: CdtAB mechanism of intoxication; post invasion (5)

A
  1. when endosome pH drops, CdtB forms pore in endosome membrane
  2. CdtA translocates through pore
  3. CtdA ADP-ribosylates G-actin
  4. ADP-ribosylated G-actin caps growing actin polymer
  5. released monomers are also ADP-ribosylated
54
Q

how does actin polymerization occur (2)

A
  • actin get polymerized at one end of the polymer
  • actin monomers are released at the other end
55
Q

C. difficile: what is the results of the CdtAB intoxication (2)

A
  • actin is now trapped in ADP-ribosylated form
  • complete breakdown of microfilament network occurs
56
Q

how do you prevent C. difficile infection (2)

A
  • limit antibiotic usage
  • increase hygiene practices
57
Q

CDI treatment (acute) (2)

A
  • patients with diarrhea tested for TcdA and TcdB
  • antibiotics can be used
58
Q

when do CDI treatment fail

A
  • failure to restore a stable, healthy microbiota after antibiotic treatment results in relapse
59
Q

CDI treatment (chronic)

A
  • fecal microbiota transplant (FMT)

MICB 308 (22 decks)

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