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Flashcards in Microbial Toxins Deck (40)
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1

Molecular version of Koch's Postulates

1. Show toxin production is associated with pathogenic species / strain of microbe.
2. Show inactivation of virulence factor gene --> decreased virulence
3. Show replacement of mutated gene w/ wild type allele restores wild type virulence levels

2

Two main categories of Microbial Toxins

1. Bacterial Protein Toxins
2. LPS of Gram Negative bacteria

3

General properties of Bact. Protein toxins

1. heat-labile
2. immunogenic
3. neutralized by specific Ab

"Exotoxins" = secreted or spilled at lysis

4

General properties of LPS toxins

1. is a PAMP - recog. by TLR4
2. Response pathway involves LPS binding protein, TLR4, CD14 + other.
3. Low Dose - fever, acute phase inflamm., polyclonal Ab production, activate Macs, B-cells, alternative complement pathway
4. High Dose - Shock, DIC, cytokine mediated effects

5

Toxic enzymes such as hyaluronidase, collagenase, elastase, deoxyribonuclease and streptokinase act by...

break down extra cellular matrix and degrade debris, enhancing spread of microbe.

6

Toxins that damage cell membranes usually do what to cells...

kill them

7

Fancy names for toxins that damage cell membranes...

hemolysins - so named b/c seen to lyse RBCs
Lecithinases
Cytolysins - lyse a variety of cells

8

Action of Cytolysins...

insert into membrane, form pore --> lysis

9

Action of Lecithinases

degrade cell membrane components, disrupt membrane integrity

10

Toxins that stimulate cytokine production...fancy name.

Superantigens
ex: Pyrogenic exotoxins

11

Superantigen Action

Bind MHC II and T-Cells (V_beta chain)
Activate LOTS of T Cells,
Cytokine release (excessive) IL-2, IFN-gamma

12

Diphtheria Toxin & Pseudomonas aeruginosa Exotoxin A action...

ENTER CELL
inactivate elongation factor 2 (EF-2) thus INHIBIT PROTEIN SYNTHESIS
Are ADP ribosyltransferases: transfer ADP-ribose from NAD to modified histidine residue (diphthamide) of EF-2, thus inactivating EF-2

13

Shiga toxin is released by which two microbes?

Shigella dysenteriae
E. Coli (gram neg. rod :)

14

Shiga toxin action

RNA N-glycosidases
remove a particular adenine residue from 28S RNA of 60S rib. subunit --> inactivate ribosomes --> INHIBIT PROTEIN SYNTHESIS

15

What plant toxin has the same action as Shiga toxin?

Ricin

16

Name 7 toxins that alter intracellular signaling pathways.

1. Heat-labile enterotoxins of Vibrio cholerare and E. Coli
2. Pertussins toxin
3. Heat-stable enterotoxin I (ST-I) of E. Coli
4. Anthrax edema factor (EF) of Bacillus anthracis 5. Adenylate cyclase toxin from bordetella pertussis
6. Anthrax lethal factor (LF) from bacillus anthracis
7. C. diff- toxins A & B

17

Action of Heat-labile enterotoxins of Vibrio cholerae and E. coli

ADP ribosyltransferases ---> activate alpha subuint of stimulatory G_s regulatory protein -->increased intracellular cAMP in small intestinal enterocytes --> active chloride secretion ---> secretory diarrhea

18

Action of Pertussin toxin (PTx)

ADP ribosyltransferase --> inactivate alpha subunit of inhibitory G_i --> increased intracellular cAMP --> tissue specific effects

End Result: inhibit host immune response. e.g. prevent phagocytosis, prevent lymphocytes from entering lymph nodes resulting in lymphocytosis

19

Action of Heat stable enterotoxin I (ST-I) of E. coli

Activate cell membrane-assoc. guanylate cyclase. increase intracellular cGMP in enterocytes --> secretory diahhrea

20

Action of Anthrax edema factor (EF)
Bacillus anthracis.

Requires what host-cell contents to activate?

Adenylate cyclases
enter target cells
increase intracellular cAMP --> cAMP dependent effects
REQUIRES ACTIVATION BY CALMODULIN AND CALCIUM

21

Action of Bordetella pertussis adenylate cyclase toxin (PTx) requires what host-cell contents to activate?

same as Anthrax EF
increase cAMP --> cAMP-dependent effects
REQUIRES ACTIVATION BY CALMODULIN AND CALCIUM

22

Action of Anthrax lethal factor (LF)

endopeptidase
cleaves MAP kinase kinase proteins, inactivates their fn. in signal transduction
...contribution to lethal effects in cardiac muscle cells and vasculature.

23

Action of C. diff toxins A & B

glucosyl transferases
alter actin cytoskeleton
transfer glucose from UDP-glucose to Rho family GTPases ---inactivating them

24

Action of Botulinum toxin...how many antigenic types and which ones cause dx in humans?

Flaccid paralysis (skeletal muscles)
inhibit Ach release and myoneural junction

A,B,E cause dx

25

Action of Tetanus toxin.
How many antigenic types?

Contractile paralysis
inhibit neurotransmitter release at inhibitory interneurons in spinal cord

only one antigenic type

26

Tetanus toxin and botulinum toxins have this in common...

zinc-dependent endopeptidases
inactivate SNARE proteins --> inhibity neuroexocytosis (VAMP = synaptobrevin, SNAP-25 and syntaxin) via serotype-specific protein cleavage

(thankyou Dr. Prekeris)

27

How is Botulinum toxin used therapeutically?

tx: focal dystonias (e.g. parkinsons pts on certain meds experience this as a side effect and get botox injections as tx)

also, cosmetic

28

Toxins that act intracellularly have what general structure?

bifunctional proteins with separate domains (subuints)
A = active domain
B = binding domain

29

Susceptibility / Resistance of a target cell to a specific toxin depends on what?

presence or absence of receptors on cell membrane

30

What do toxins generally use as receptors?

they've evolved to take advantage of normal membrane constituents.