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Bacterial

Toxins

Classification
Dr.Faghri
Meisam.Roozbahani
Introduction


Toxins were the first bacterial virulence factors to
be identified and were also the first link between
bacteria and cell biology.
Introduction


Cellular microbiology was, in fact, naturally born
a long time ago with the study of toxins, and only
recently, thanks to the sophisticated new
technologies, has it expanded to include the study
of many other aspects of the interactions
between bacteria and host cells.
Two Main Categories of Toxins
Specific Host Site Exotoxins


Neurotoxins



Enterotoxins



Cytotoxins


Nephrotoxin



Hepatotoxin



Cardiotoxin
Classification by Entrance Mechanism
Injected into
eukaryotic cells

Protein synthesis

Mediators of apoptosis

Surface molecules

Signal transduction

Inositol phosphate
metabolism

Cell membrane

Class

Acting on
intracellular
targets

Immune system
(Superantigens)

Target

Acting on the
cell surface

Cytoskeleton structure

Cytoskeleton

Large pore- forming toxins

Intracellular trafficking

Signal transduction

Small pore- forming toxins
RTX toxins
Membrane-perturbing
toxins
Other pore- forming
toxins
Insecticidal toxins

Unknown
mechanism of
action
Toxins acting on the cell surface:
Immune system (Superantigens)


Superantigens are bacterial
and viral proteins that share
the ability to activate a large
fraction of T-lymphocytes.
Toxins acting on the cell surface: Immune system (Superantigens)
Toxin

Organism

Activity

Consequence

Binding to MHC class II
molecules and to Vβ or Vγ
of T cell receptor

T cell activation and
cytokines secretion

MAM

Mycoplasma
arthritidis

Binding to MHC class II
molecules and to Vβ or Vγ
of T cell receptor

Chronic inflammation

YPMa

Yersinia
pseudotuberculosis

Binding to MHC class II
molecules and to Vβ or Vγ
of T cell receptor

Chronic Inflammation

S. pyogenes

Cysteine protease

Alteration in
Immunoglobulin binding
properties

S. aureus

Trypsin-like serine
proteases

T-cell proliferation,
intraepidermal layer
separation

SEA-SEI, TSST-1, SPEA,
Staphylococcus
SPEC, SPEL, SPEM, SSA, and aureus and Streptococcus
SMEZ
pyogenes

SPEB

ETA, ETB, and ETD
Agr Regulatory System
Toxins acting on the cell surface:
Surface molecules


BFT enterotoxin: The pathogenicity of ETBF is
ascribed to a heat-labile ∼20-kDa toxin (B.
fragilis toxin [BFT], also called fragilysin).



This toxin binds to a specific intestinal epithelial
cell receptor and stimulates cell proliferation.
BFT enterotoxin
Toxins acting on the cell surface: Surface molecules
Toxin

Organism

Activity

Consequence

BFT enterotoxin

Bacteroides fragilis

Metalloprotease, cleavage
of E-cadherin

Alteration of epithelial
permeability

AhyB

Aeromonas
hydrophyla

Elastase,
metalloprotease

Hydrolization of casein and
elastine

Aminopeptidase

Pseudomonas
aeruginosa

Elastase,
metalloprotease

Corneal infection,
inflammation and
ulceration

ColH

Clostridium
histolyticum

Collagenase,
metalloprotease

Collagenolytic activity

Nhe

Bacillus cereus

Metalloprotease and
collagenase

Collagenolytic activity
Toxins acting on the cell surface:
Pore-Forming


Protein toxins forming pores in biological membranes
occur frequently in Gram-positive and Gram-negative
bacteria.



Pore-forming toxins, also known as "lytic factors".



Some of them are also called "hemolysins“.
Toxins acting on the cell surface:
Large Pore-Forming Toxins


Generally secreted by diverse species of Grampositive bacteria.



Binding selectively to cholesterol on the
eukaryotic cell membrane.
Toxins acting on the cell surface: Large pore forming toxins
Toxin

Organism

Activity

Consequence

PFO

C. perfringens

Thiol-activated cytolysin,
cholesterol Binding

Gas gangrene

SLO

S. pyogenes

Thiol-activated cytolysin,
cholesterol Binding

Transfer of other toxins,
cell death

Induction of Lymphocyte
apoptosis

Membrane damage

Induction of Lymphocyte
Apoptosis

Complement activation,
cytokine production,
apoptosis

LLO
Pneumolysin

Listeria monocytogenes
S. pneumoniae
Toxins acting on the cell surface:
Small pore forming toxins


Creating very small pores 1-1.5 nm diameter.



Selective permeabilization to solutes with a molecular
mass less than 2 kDa.
Toxins acting on the cell surface: Small pore forming toxins
Toxin

Organism

Activity

Consequence

Alveolysin

B. alveis

Induction of lymphocyte Apoptosis

Complement activation, cytokine
production, apoptosis

ALO

B. anthracis

Induction of lymphocyte apoptosis

Complement activation, cytokine
production, Apoptosis

α-Toxin

S. aureus

Binding of erythrocytes

Release of cytokines, cell lysis, apoptosis

PVL leukocidin
(LukS-LukF)

S. aureus

Cell membrane permeabilization

Necrotic enteritis, rapid shock-like
syndrome

γ-Hemolysins
(HlgA- HlgB and
HlgC- HlgB)

S. aureus

Cell membrane permeabilization

Necrotic enteritis, rapid shock-like
syndrome

β-Toxin

C. perfringens

Cell membrane permeabilization

Necrotic enteritis, neurologic effects
Toxins acting on the cell surface:
RTX toxins


The RTX toxin family is a group of cytotoxins produced by
Gram-negative bacteria.



There are over 1000 known members with a variety of
functions.
Toxins acting on the cell surface:
RTX toxins


The RTX family is defined by two common features:
characteristic repeats in the toxin protein sequences, and
extracellular secretion by the type I secretion system
(T1SS).



The name RTX (repeats in toxin) refers to the glycine and
aspartate-rich repeats located at the C-terminus of the
toxin proteins.
Genomic Structure


The toxin is encoded by four genes, one of which, hlyA,
encodes the 110-kDa hemolysin. The other genes are
required for its posttranslational modification (hlyC) and
secretion (hlyB and hlyD).
Toxins acting on the cell surface: RTX toxins
Toxin

Organism

Activity

Consequence

Hemolysin II

B. cereus

Cell membrane permeabilization

Hemolytic activity

CytK

B. cereus

Cell membrane Permeabilization

Necrotic enteritis

HlyA

E. coli

Calcium-dependent formation of transmembrane Pores

Cell permeabilization and lysis
Toxins acting on the cell surface:
Membrane perturbing toxins


Soap like structure.



The toxin binds nonspecifically parallel to the surface of
any membrane without forming transmembrane channels.



Cells first become permeable to small solutes and
eventually swell and lyse, releasing cell intracellular
content.
Toxins acting on the cell surface: Membrane perturbing toxins
Toxin

Organism

Activity

Consequence

ApxI, ApxII, and ApxIII A.pleuropneumoniae

Calcium-dependent formation of
transmembrane Pores

Lysis of erythrocytes and
other nucleated Cells

LtxA

A.actinomycetemcomitans

Calcium-dependent formation of
transmembrane Pores

Apoptosis

LtxA

P.Haemolytica

Calcium-dependent formation of
transmembrane Pores

Activity specific versus
ruminant leukocytes
Toxins acting on the cell surface:
Other pore forming toxins


Like other functionally related toxins, aerolysin changes
its topology in a multi-step process from a completely
water-soluble form to a membrane-soluble heptameric
transmembrane channel that destroys sensitive cells by
breaking their permeability barriers.
Toxins acting on the cell surface: Other pore forming toxins
Toxin

Organism

Activity

Consequence

δ-Hemolysin

S. aureus

Perturbation of the lipid bilayer

Cell permeabilization and lysis

Aerolysin

A. hydrophila

Perturbation of the lipid bilayer

Cell permeabilization and lysis

AT

C. septicum

Perturbation of the lipid bilayer

Cellpermeabilization and lysis
Toxins acting on the cell surface:
Insecticidal toxins


The class of insecticidal proteins, also known as
δ-endotoxins, includes a number of toxins produced by
species of Bacillus thuringiensis.



These exert their toxic activity by making pores in the
epithelial cell membrane of the insect midgut.
Toxins acting on the cell surface:
Insecticidal toxins


δ-Endotoxins form two multigenic families, cry and cyt;


members of the cry family are toxic to insects of
Lepidoptera, Diptera and Coleoptera orders (Hofmann et al.,
1988),



whereas members of the cyt family are lethal specifically to
the larvae of Dipteran insects (Koni and Ellar, 1994).

Lepidoptera is a large order of insects that includes moths and butterflies.
True flies are insects of the order Diptera.
Coleoptera is an order of insects commonly called beetles.
Toxins acting on the cell surface: Insecticidal toxins
Toxin

Organism

Activity

Consequence

PA

B. anthracis

Perturbation of the lipid bilayer

Cell permeabilization and lysis

HlyE

E. coli

Perturbation of the lipid bilayer

Osmotic lysis of cells lining the Midgut

CryIA, CryIIA,
CryIIIA, etc

Bacillus thuringiensis

Destruction of the transmembrane
Potential

Osmotic lysis of cells lining the Midgut

CytA, CytB

B. thuringiensis

Destruction of the transmembrane
Potential

Osmotic lysis of cells lining the Midgut

BT toxin

B. thuringiensis

Destruction of the transmembrane
Potential

Cytocidal activity on human cells
Toxins Acting on Intracellular Targets

Class

The group of toxins with an intracellular
Acting on the
target (A/B toxins) contains many toxins
cell surface
with different structures that have only
one general feature in common: they are
Immune system
composed of two domains generally
(Superantigens)
identified as "A" and "B.“

Acting on
intracellular
targets

Injecte
eukaryo

Protein synthesis

Mediators o

Inositol ph
metab

Surface molecules

Signal transduction

Cell membrane

arget



Cytoskeleton structure

Cytoske

Large pore- forming toxins

Intracellular trafficking

Signal tran

Small pore- forming toxins
Toxins Acting on Intracellular Targets


The A domain is the active portion of the toxin; it usually
has enzymatic activity and can recognize and modify a
target molecule within the cytosol of eukaryotic cells.



The B domain is usually the carrier for the A subunit; it
bind the receptor on the cell surface and facilitates the
translocation of A across the cytoplasmic membrane.
Toxins acting on intracellular targets:
Protein synthesis


These toxins are able to cause rapid cell death at
extremely low concentrations.



This reaction leads to the formation of a completely
inactive EF2-ADP-ribose complex.
Toxins acting on intracellular targets:
Protein synthesis


A very important step in the elucidation of the mechanism
of enzymatic activity has been the determination of the
crystal structure for the complex of diphtheria toxin with
NAD.



Upon the addition of NAD to nucleotide-free DT crystals, a
significant structural change.



This change lead to recognition and binding of the
acceptor substrate EF-2.



This would explain why DT recognizes EF-2 only after NAD
has bound.
Toxins acting on intracellular targets: Protein synthesis
Toxin

Organism

Activity

Toxins acting on intracellular targets:
Corynebacterium diphtheriae
ADP-ribosylation of EF-2
PAETA P. aeruginosa
Protein synthesis ADP-ribosylation of EF-2
DT

SHT

S. dysenteriae

N-glycosidase activity on 28S RNA

Consequence
Cell death
Cell death
Cell death, apoptosis
Toxins acting on intracellular targets:
Signal transduction


Two types of transduction mechanism:


Tyrosine phosphorylation



Modification of a receptor-coupled GTP-binding protein


cyclic AMP



inositol triphosphate



diacylglycerol
Pertussis toxin

PT Subunits
A

B
Cholera toxin (CT) and E. coli heatlabile enterotoxins (LT-I and LT-II)


Cholera toxin (CT) and E. coli heat-labile enterotoxins (LTI and LT-II) share an identical mechanism of action and
homologous primary and 3D structures.



While V. cholerae exports the CT toxin into the culture
medium, LT remains associated to the outer membrane
bound to lipopolysaccharide.



The corresponding genes of CT and LT are organized in a
bicistronic operon and are located on a filamentous
bacteriophage and on a plasmid, respectively.
Clostridium difficile Toxins


Enterotoxin A (TcdA) and cytotoxin B (TcdB) of Clostridium
difficile are the two virulence factors responsible for the
induction of antibiotic-associated diarrhea.



The toxin genes tcdA and tcdB together with three
accessory genes (tcdC-E) constitute the pathogenicity
locus (PaLoc) of C. difficile.
Toxins acting on intracellular targets: Signal transduction 1
Toxin

Organism

Activity

Consequence

PT

Bordetella pertussis ADP-ribosylation of Gi

cAMP increase

CT

Vibrio cholerae

ADP-ribosylation of Gi

cAMP increase

LT

E. coli

ADP-ribosylation of Gi

cAMP increase

α-Toxin (PLC)

C. perfringens

Zinc-phospholipase C, hydrolase

Gas gangrene

Toxins A and B (TcdA and
TcdB)

C. difficile

Monoglucosylation of Rho, Rac,
Cdc42

Breakdown of cellular actin
stress fibers

Adenylate cyclase (CyaA)

B. pertussis

Binding to calmodulin ATP→cAMP
conversion

cAMP increase
Anthrax Edema and Lethal Factors


The EF and LF genes are located on a large plasmids.



Cleavage of the N-terminal signal peptides yields mature
EF and LF proteins.



LF, is able to cause apoptosis in human endothelial cells.
E. coli Cytotoxin Necrotizing Factors and
Bordetella Dermonecrotic Toxin


CNF1 & CNF2: produced by a number of uropathogenic
and neonatal meningitis-causing pathogenic E. coli
strains.



cnf1 is chromosomally encoded, cnf2 is carried on a
large transmissible F-like plasmid called "Vir“.



DNT is a transglutaminase, which causes alteration of
cell morphology, reorganization of stress fibers, and
focal adhesions on a variety of animal models.
Cytolethal Distending Toxins


HdCDT is a complex of three proteins (CdtA, CdtB and
CdtC) encoded by three genes that are part of an operon.



Members of this family have been identified in E. coli,
Shigella, Salmonella, Campylobacter, Actinobacillus and
Helicobacter hepaticus.
Toxins acting on intracellular targets: Signal transduction 2
Toxin

Organism

Activity

Consequence

Anthrax edema factor (EF)

B. anthracis

Binding to calmodulin ATP→cAMP
conversion

cAMP increase

Anthrax lethal factor (LF)

B. anthracis

Cleavage of MAPKK1 and MAPKK2

Cell death, apoptosis

Cytotoxin necrotizing
factors 1 and 2 (CNF1, 2)

E. coli

Deamidation of Rho, Rac and Cdc42

Ruffling, stress fiber
formation.

DNT

Bordetella species

Transglutaminase, deamidation or
polyamination of Rho GTPase

Ruffling, stress fiber
formation

CDT

Several species

DNA damage, formation of actin
stress fibers via activation of RhoA

Cell-cycle arrest,
cytotoxicity, apoptosis
Toxins acting on intracellular targets:
Cytoskeleton structure


The cytoskeleton is a cellular structure that consists of a
fiber network composed of microfilaments, microtubules,
and the intermediate filaments.



It controls a number of essential functions in the
eukaryotic cell:


exo- and endocytosis



vesicle transport



cell-cell contact



and mitosis
Toxins acting on intracellular targets:
Cytoskeleton structure


Most of them do it by modifying the regulatory, small G
proteins, such as Ras, Rho, and Cdc42, which control cell
shape.
Lymphostatin


Lymphostatin is a very recently identified protein in
enteropathogenic strains of E. coli



Lymphostatin selectively block the production of
interleukin-2, IL-4, IL-5 and γ interferon by human cells
and inhibit proliferation of these cells, thus interfering
with the cellular immune response.
Toxins acting on intracellular targets: Cytoskeleton structure
Toxin

Organism

Activity

Toxin C2 and related
proteins

C. botulinum

ADP-ribosylation of monomeric G actin Failure in actin polymerization

Lymphostatin

E. coli

Block of interleukin production

Chronic diarrhea

Block of interleukin production

Chronic diarrhea

Iota toxin and related
C. perfringens
proteins

Consequence
Toxins acting on intracellular targets:
Intracellular trafficking


Vesicle structures are essential in:





receptor-mediated endocytosis
and exocytosis

One example of exocytic pathway is that involving the
release of neurotransmitters
Mechanism of action of clostridial
neurotoxins (CNT)

Synaptosomal-associated protein 25 (SNAP-25)
Helicobacter pylori Vacuolating
Cytotoxin Vac A


This toxin is responsible for massive growth
of vacuoles within epithelial cells.



VacA can insert into membranes forming
hexameric, anion-selective pores.
Toxins acting on intracellular targets: Intracellular trafficking
Toxin

Organism

Activity

Consequence

TeNT

C. tetanii

Cleavage of VAMP/ synaptobrevin

Spastic paralysis

BoNT-B, D, G and F
neurotoxins

C. botulinum

Cleavage of VAMP/ synaptobrevin

Flaccid paralysis

BoNT-A, E neurotoxins

C. botulinum

Cleavage of SNAP-25

Flaccid paralysis

BoNT-C neurotoxin

C. botulinum

Cleavage of syntaxin, SNAP-25

Flaccid paralysis

Vacuolating cytotoxin
VacA

H. pylori

Alteration in the endocytic pathway

Vacuole formation,
apoptosis

NAD glycohydrolase

S. pyogenes

Keratinocyte apoptosis

Enhancement of GAS
proliferation
Toxins injected into eukaryotic cells


These bacteria intoxicate individual eukaryotic cells by
using a contact-dependent secretion system to inject or
deliver toxic proteins into the cytoplasm of eukaryotic
cells.



This is done by using specialized secretion systems that in
Gram-negative bacteria are called "type III" or "type IV,“.
Class

Toxins injected into eukaryotic cells:
Acting on
Acting on the
Mediators of apoptosis: IpaB in Shigella
intracellular


cell surface

targets

Shigella invasion plasmid antigen (Ipa) proteins: IpaA,
Immune
IpaB, IpaC, IpaD. system
Protein synthesis
(Superantigens)

Only IpaB is required to initiate cell death.

Mediators of apoptosis

Surface molecules

Signal transduction

Inositol phosphate
metabolism

Cell membrane

Target



Injected into
eukaryotic cells

Cytoskeleton structure

Cytoskeleton

Large pore- forming toxins

Intracellular trafficking

Signal transduction

Small pore- forming toxins
RTX toxins
Membrane-perturbing
toxins
Toxins injected into eukaryotic cells:
Mediators of apoptosis: SipB in Salmonella


An analog of Shigella invasin IpaB.



In contrast to Shigella, Salmonella does not escape from
the phagosome, but it survives and multiplies within the
macrophages.



Salmonella virulence genes are encoded by a chromosomal
operon named sip containing five genes (sipEBCDA).
Toxins injected into eukaryotic cells: Mediators of apoptosis
Toxin

Organism

Activity

Consequence

IpaB

Shigella

Binding to ICE

Apoptosis

SipB

Salmonella

Cysteine proteases

Apoptosis

YopP/YopJ

Yersinia species

Cysteine protease, blocks MAPK and NFkappaB pathways

Apoptosis
Toxins injected into eukaryotic cells:
Inositol phosphate metabolism


SopB: in Salmonella is homologous to the Shigella flexneri
lpgD virulence factor.



Both proteins contain two regions of sequence similarities
with human inositol polyphosphatases types I and II.
Toxins injected into eukaryotic cells: Inositol phosphate metabolism
Toxin

Organism

Activity

Consequence

SopB

Salmonella
species

Inositol phosphate phosphatase, cytoskeleton
rearrangements

Increased chloride
secretion (diarrhea)

IpgD

S. flexneri

Inositol phosphate phosphatase, cytoskeleton
rearrangements

Increased chloride
secretion (diarrhea)
Toxins injected into eukaryotic cells: Signal transduction
Toxin

Organism

Activity

Consequence

ExoS

P. aeruginosa

ADP-ribosylation of Ras, Rho GTPase

Collapse of cytoskeleton

C3 exotoxin

C. botulinum

ADP-ribosylation of Rho

Breakdown of cellular actin stress
fibers

ADP-ribosylation of Rho

Modification of actin cytoskeleton

Rac and Cdc42 activation

Membrane ruffling, cytoskeletal
reorganization, proinflammatory
cytokines production

EDIN-A, B and C S. aureus
SopE

S.
typhimurium

SipA

S.
typhimurium

Rac and Cdc42 activation

Membrane ruffling, cytoskeletal
reorganization, proinflammatory
cytokines production

IpaA

Shigella
species

Vinculin binding

Depolymerization of actin filaments

YopE

Yersinia
species

GAP activity towards RhoA, Rac1 or Cdc42

Cytotoxicity, actin depolymerization

YopT

Yersinia
species

Cysteine protease, cleaves RhoA, Rac, and
Cdc42 releasing them from the membrane

Disruption of actin cytoskeleton

VirA

Shigella
flexneri

Inhibition of tubulin polymerization

Microtubule destabilization and
membrane ruffling
Toxins injected into eukaryotic cells: Signal transduction
Toxin

Organism

Activity

Consequence

YpkA

Yersinia species

Protein serine/threonine kinase

Inhibition of phagocytosis

YopH

Yersinia species

Tyrosine phosphatase

Inhibition of phagocytosis

Tir

E. coli EPEC

Receptor for intimin

Actin nucleation and pedestalformation

CagA

H. pylori

Tyrosine phosphorylated

Cortactin dephosphorylation

YopM

Yersinia species

Interaction with PRK2 and RSK1 kinases

Cytotoxicity

SptP

S. typhimurium

Inhibition of the MAP kinase pathway

Enhancement of Salmonella capacity to
induce TNF-alpha secretion

ExoU

P. aeruginosa

Lysophospholipase A activity

Lung injury
Toxins with unknown mechanism of action
Toxin

Organism

Activity

Consequence

Zot

V. cholerae

?

Modification of intestinal tight junction
permeability

Hemolysin
BL (HBL)

B. cereus

Hemolytic, dermonecrotic and
vascular permeability activities

Food poisoning, fluid accumulation and
diarrhea

BSH

L. monocytogenes ?

Increased bacterial survival and intestinal
colonization
Abbreviations
SEA-SEI, staphylococcal enterotoxins

SHT, Shiga toxin;

TSST, toxic shock syndrome toxin

PT, pertussis toxin;

SPE, streptococcal exotoxin

CT, cholera toxin;

SSA, streptococcal superantigen

LT, heat-labile enterotoxin;

SMEZ, streptococcal mitogenic exotoxin z

DNT, dermonecrotic toxin;

MAM, Mycoplasma arthritidis mitogen

CDT, cytolethal distending toxin;

YPMa, Y. pseudotuberculosis-derived mitogen

TeNT, tetanus neurotoxin;

ETA and ETB, exfoliative toxins

RTX, repeats in the structural toxin;

ColH, collagenase

Hly, hemolysin;

Nhe, nonhemolytic entertoxin

Cry, crystal;

PFO, perfringolysin O;

BoNT, botulinum neurotoxin;

SLO, streptolysin O;

Ipa, invasion plasmid antigen;
Abbreviations
LLO, listeriolysin O;

Sip, Salmonella invasion protein;

ALO, anthrolisin O;

EDIN, epidermal cell differentiation inhibitor;

AT, α-toxin;

Sop, Salmonella outer protein;

PA, protective antigen;

Ipg, invasion plasmid gene;

DT, diphtheria toxin;

Yop, Yersinia outer protein;

PAETA, Pseudomonas aeruginosa exotoxin A;

GAP, GTPase-activating protein;

GAS, group A Streptococcus;

Vir, virulence protein;

YpkA, Yersinia protein kinase A;

Tir, translocated intimin receptor;

EPEC, enteropathogenic E. coli;

CagA, cytotoxin-associated gene A;

SptP, Salmonella protein tyrosine phosphatase;

VAMP, vesicle-associated membrane protein;

ICE, interleukin-1β-converting enzyme;

SNAP, synaptosome-associated protein;

MAPKK, mitogen-activated protein kinase ;

Zot, zonula. occludens toxin; and BSH, bile salt hydrolase.
Enzymatic activities
Glucosyl-transferases
Deamidases
ADP-ribosyltransferases

N-Glycosidases
Metalloproteases
Substrate

Effect

DT

ADP-ribosyltransferases

Toxin

Elongation factor EF-2

Cell death

PAETA

Elongation factor EF-2

Cell death

PT

Gi, Go and transducin

cAMP increase

CT

Gs, Gt and Golf
E. coli LT
Clostridium botulinum C2

Actin

Failure in actin

P. aeruginosa ExoS

Ras

Collapse of cytoskeleton

Clostridium botulinum C3

Rho

Breakdown of cellular actin stress
fibers
Toxin

Effect

Clostridium difficile toxins A and B

Rho/Ras GTPases

Breakdown of cytoskeletal structure

E. coli CNF1

Glucosyl-transferases

Substrate

Rho, Rac and CdC42
Stress fiber formation

Deamidases
Bordetella DNT

Metalloproteases

Shiga toxin

Ribosomal RNA

Stop of protein synthesis

Bacillus anthracis LF

N-Glycosidases

Rho,

Macrophages

Disruption of normal homoeostatic
functions

Clostridium tetanii TeNT

VAMP/synaptobrevin

Spastic paralysis

C. botulinum BoNTs

VAMP/synaptobrevin, SNAP-25

Flaccid paralysis
Abbreviations
SNAP-25, synaptosome-associated protein of 25 kDa.

CNF1, cytotoxin necrotizing factor 1;

DNT, dermonecrotic factor;

DT, diphtheria toxin;

PAETA, Pseudomonas aeruginosa exotoxin A;

PT, pertussis toxin;

CT, cholera toxin;

LT, heat-labile enterotoxin;

ExoS, exoenzyme S;

LF, lethal factor;

TeNT, tetanus neurotoxin;

BoNT, botulinum neurotoxin;

VAMP, vesicle associated membrane protein;
Thank You

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Bacterial Toxins and Toxin classification

  • 2. Introduction  Toxins were the first bacterial virulence factors to be identified and were also the first link between bacteria and cell biology.
  • 3. Introduction  Cellular microbiology was, in fact, naturally born a long time ago with the study of toxins, and only recently, thanks to the sophisticated new technologies, has it expanded to include the study of many other aspects of the interactions between bacteria and host cells.
  • 5.
  • 6.
  • 7. Specific Host Site Exotoxins  Neurotoxins  Enterotoxins  Cytotoxins  Nephrotoxin  Hepatotoxin  Cardiotoxin
  • 9. Injected into eukaryotic cells Protein synthesis Mediators of apoptosis Surface molecules Signal transduction Inositol phosphate metabolism Cell membrane Class Acting on intracellular targets Immune system (Superantigens) Target Acting on the cell surface Cytoskeleton structure Cytoskeleton Large pore- forming toxins Intracellular trafficking Signal transduction Small pore- forming toxins RTX toxins Membrane-perturbing toxins Other pore- forming toxins Insecticidal toxins Unknown mechanism of action
  • 10. Toxins acting on the cell surface: Immune system (Superantigens)  Superantigens are bacterial and viral proteins that share the ability to activate a large fraction of T-lymphocytes.
  • 11. Toxins acting on the cell surface: Immune system (Superantigens) Toxin Organism Activity Consequence Binding to MHC class II molecules and to Vβ or Vγ of T cell receptor T cell activation and cytokines secretion MAM Mycoplasma arthritidis Binding to MHC class II molecules and to Vβ or Vγ of T cell receptor Chronic inflammation YPMa Yersinia pseudotuberculosis Binding to MHC class II molecules and to Vβ or Vγ of T cell receptor Chronic Inflammation S. pyogenes Cysteine protease Alteration in Immunoglobulin binding properties S. aureus Trypsin-like serine proteases T-cell proliferation, intraepidermal layer separation SEA-SEI, TSST-1, SPEA, Staphylococcus SPEC, SPEL, SPEM, SSA, and aureus and Streptococcus SMEZ pyogenes SPEB ETA, ETB, and ETD
  • 13. Toxins acting on the cell surface: Surface molecules  BFT enterotoxin: The pathogenicity of ETBF is ascribed to a heat-labile ∼20-kDa toxin (B. fragilis toxin [BFT], also called fragilysin).  This toxin binds to a specific intestinal epithelial cell receptor and stimulates cell proliferation.
  • 15. Toxins acting on the cell surface: Surface molecules Toxin Organism Activity Consequence BFT enterotoxin Bacteroides fragilis Metalloprotease, cleavage of E-cadherin Alteration of epithelial permeability AhyB Aeromonas hydrophyla Elastase, metalloprotease Hydrolization of casein and elastine Aminopeptidase Pseudomonas aeruginosa Elastase, metalloprotease Corneal infection, inflammation and ulceration ColH Clostridium histolyticum Collagenase, metalloprotease Collagenolytic activity Nhe Bacillus cereus Metalloprotease and collagenase Collagenolytic activity
  • 16. Toxins acting on the cell surface: Pore-Forming  Protein toxins forming pores in biological membranes occur frequently in Gram-positive and Gram-negative bacteria.  Pore-forming toxins, also known as "lytic factors".  Some of them are also called "hemolysins“.
  • 17. Toxins acting on the cell surface: Large Pore-Forming Toxins  Generally secreted by diverse species of Grampositive bacteria.  Binding selectively to cholesterol on the eukaryotic cell membrane.
  • 18. Toxins acting on the cell surface: Large pore forming toxins Toxin Organism Activity Consequence PFO C. perfringens Thiol-activated cytolysin, cholesterol Binding Gas gangrene SLO S. pyogenes Thiol-activated cytolysin, cholesterol Binding Transfer of other toxins, cell death Induction of Lymphocyte apoptosis Membrane damage Induction of Lymphocyte Apoptosis Complement activation, cytokine production, apoptosis LLO Pneumolysin Listeria monocytogenes S. pneumoniae
  • 19. Toxins acting on the cell surface: Small pore forming toxins  Creating very small pores 1-1.5 nm diameter.  Selective permeabilization to solutes with a molecular mass less than 2 kDa.
  • 20. Toxins acting on the cell surface: Small pore forming toxins Toxin Organism Activity Consequence Alveolysin B. alveis Induction of lymphocyte Apoptosis Complement activation, cytokine production, apoptosis ALO B. anthracis Induction of lymphocyte apoptosis Complement activation, cytokine production, Apoptosis α-Toxin S. aureus Binding of erythrocytes Release of cytokines, cell lysis, apoptosis PVL leukocidin (LukS-LukF) S. aureus Cell membrane permeabilization Necrotic enteritis, rapid shock-like syndrome γ-Hemolysins (HlgA- HlgB and HlgC- HlgB) S. aureus Cell membrane permeabilization Necrotic enteritis, rapid shock-like syndrome β-Toxin C. perfringens Cell membrane permeabilization Necrotic enteritis, neurologic effects
  • 21. Toxins acting on the cell surface: RTX toxins  The RTX toxin family is a group of cytotoxins produced by Gram-negative bacteria.  There are over 1000 known members with a variety of functions.
  • 22. Toxins acting on the cell surface: RTX toxins  The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion system (T1SS).  The name RTX (repeats in toxin) refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins.
  • 23. Genomic Structure  The toxin is encoded by four genes, one of which, hlyA, encodes the 110-kDa hemolysin. The other genes are required for its posttranslational modification (hlyC) and secretion (hlyB and hlyD).
  • 24. Toxins acting on the cell surface: RTX toxins Toxin Organism Activity Consequence Hemolysin II B. cereus Cell membrane permeabilization Hemolytic activity CytK B. cereus Cell membrane Permeabilization Necrotic enteritis HlyA E. coli Calcium-dependent formation of transmembrane Pores Cell permeabilization and lysis
  • 25. Toxins acting on the cell surface: Membrane perturbing toxins  Soap like structure.  The toxin binds nonspecifically parallel to the surface of any membrane without forming transmembrane channels.  Cells first become permeable to small solutes and eventually swell and lyse, releasing cell intracellular content.
  • 26. Toxins acting on the cell surface: Membrane perturbing toxins Toxin Organism Activity Consequence ApxI, ApxII, and ApxIII A.pleuropneumoniae Calcium-dependent formation of transmembrane Pores Lysis of erythrocytes and other nucleated Cells LtxA A.actinomycetemcomitans Calcium-dependent formation of transmembrane Pores Apoptosis LtxA P.Haemolytica Calcium-dependent formation of transmembrane Pores Activity specific versus ruminant leukocytes
  • 27. Toxins acting on the cell surface: Other pore forming toxins  Like other functionally related toxins, aerolysin changes its topology in a multi-step process from a completely water-soluble form to a membrane-soluble heptameric transmembrane channel that destroys sensitive cells by breaking their permeability barriers.
  • 28. Toxins acting on the cell surface: Other pore forming toxins Toxin Organism Activity Consequence δ-Hemolysin S. aureus Perturbation of the lipid bilayer Cell permeabilization and lysis Aerolysin A. hydrophila Perturbation of the lipid bilayer Cell permeabilization and lysis AT C. septicum Perturbation of the lipid bilayer Cellpermeabilization and lysis
  • 29. Toxins acting on the cell surface: Insecticidal toxins  The class of insecticidal proteins, also known as δ-endotoxins, includes a number of toxins produced by species of Bacillus thuringiensis.  These exert their toxic activity by making pores in the epithelial cell membrane of the insect midgut.
  • 30. Toxins acting on the cell surface: Insecticidal toxins  δ-Endotoxins form two multigenic families, cry and cyt;  members of the cry family are toxic to insects of Lepidoptera, Diptera and Coleoptera orders (Hofmann et al., 1988),  whereas members of the cyt family are lethal specifically to the larvae of Dipteran insects (Koni and Ellar, 1994). Lepidoptera is a large order of insects that includes moths and butterflies. True flies are insects of the order Diptera. Coleoptera is an order of insects commonly called beetles.
  • 31. Toxins acting on the cell surface: Insecticidal toxins Toxin Organism Activity Consequence PA B. anthracis Perturbation of the lipid bilayer Cell permeabilization and lysis HlyE E. coli Perturbation of the lipid bilayer Osmotic lysis of cells lining the Midgut CryIA, CryIIA, CryIIIA, etc Bacillus thuringiensis Destruction of the transmembrane Potential Osmotic lysis of cells lining the Midgut CytA, CytB B. thuringiensis Destruction of the transmembrane Potential Osmotic lysis of cells lining the Midgut BT toxin B. thuringiensis Destruction of the transmembrane Potential Cytocidal activity on human cells
  • 32. Toxins Acting on Intracellular Targets Class The group of toxins with an intracellular Acting on the target (A/B toxins) contains many toxins cell surface with different structures that have only one general feature in common: they are Immune system composed of two domains generally (Superantigens) identified as "A" and "B.“ Acting on intracellular targets Injecte eukaryo Protein synthesis Mediators o Inositol ph metab Surface molecules Signal transduction Cell membrane arget  Cytoskeleton structure Cytoske Large pore- forming toxins Intracellular trafficking Signal tran Small pore- forming toxins
  • 33. Toxins Acting on Intracellular Targets  The A domain is the active portion of the toxin; it usually has enzymatic activity and can recognize and modify a target molecule within the cytosol of eukaryotic cells.  The B domain is usually the carrier for the A subunit; it bind the receptor on the cell surface and facilitates the translocation of A across the cytoplasmic membrane.
  • 34. Toxins acting on intracellular targets: Protein synthesis  These toxins are able to cause rapid cell death at extremely low concentrations.  This reaction leads to the formation of a completely inactive EF2-ADP-ribose complex.
  • 35. Toxins acting on intracellular targets: Protein synthesis  A very important step in the elucidation of the mechanism of enzymatic activity has been the determination of the crystal structure for the complex of diphtheria toxin with NAD.  Upon the addition of NAD to nucleotide-free DT crystals, a significant structural change.  This change lead to recognition and binding of the acceptor substrate EF-2.  This would explain why DT recognizes EF-2 only after NAD has bound.
  • 36. Toxins acting on intracellular targets: Protein synthesis Toxin Organism Activity Toxins acting on intracellular targets: Corynebacterium diphtheriae ADP-ribosylation of EF-2 PAETA P. aeruginosa Protein synthesis ADP-ribosylation of EF-2 DT SHT S. dysenteriae N-glycosidase activity on 28S RNA Consequence Cell death Cell death Cell death, apoptosis
  • 37. Toxins acting on intracellular targets: Signal transduction  Two types of transduction mechanism:  Tyrosine phosphorylation  Modification of a receptor-coupled GTP-binding protein  cyclic AMP  inositol triphosphate  diacylglycerol
  • 39. Cholera toxin (CT) and E. coli heatlabile enterotoxins (LT-I and LT-II)  Cholera toxin (CT) and E. coli heat-labile enterotoxins (LTI and LT-II) share an identical mechanism of action and homologous primary and 3D structures.  While V. cholerae exports the CT toxin into the culture medium, LT remains associated to the outer membrane bound to lipopolysaccharide.  The corresponding genes of CT and LT are organized in a bicistronic operon and are located on a filamentous bacteriophage and on a plasmid, respectively.
  • 40. Clostridium difficile Toxins  Enterotoxin A (TcdA) and cytotoxin B (TcdB) of Clostridium difficile are the two virulence factors responsible for the induction of antibiotic-associated diarrhea.  The toxin genes tcdA and tcdB together with three accessory genes (tcdC-E) constitute the pathogenicity locus (PaLoc) of C. difficile.
  • 41. Toxins acting on intracellular targets: Signal transduction 1 Toxin Organism Activity Consequence PT Bordetella pertussis ADP-ribosylation of Gi cAMP increase CT Vibrio cholerae ADP-ribosylation of Gi cAMP increase LT E. coli ADP-ribosylation of Gi cAMP increase α-Toxin (PLC) C. perfringens Zinc-phospholipase C, hydrolase Gas gangrene Toxins A and B (TcdA and TcdB) C. difficile Monoglucosylation of Rho, Rac, Cdc42 Breakdown of cellular actin stress fibers Adenylate cyclase (CyaA) B. pertussis Binding to calmodulin ATP→cAMP conversion cAMP increase
  • 42. Anthrax Edema and Lethal Factors  The EF and LF genes are located on a large plasmids.  Cleavage of the N-terminal signal peptides yields mature EF and LF proteins.  LF, is able to cause apoptosis in human endothelial cells.
  • 43. E. coli Cytotoxin Necrotizing Factors and Bordetella Dermonecrotic Toxin  CNF1 & CNF2: produced by a number of uropathogenic and neonatal meningitis-causing pathogenic E. coli strains.  cnf1 is chromosomally encoded, cnf2 is carried on a large transmissible F-like plasmid called "Vir“.  DNT is a transglutaminase, which causes alteration of cell morphology, reorganization of stress fibers, and focal adhesions on a variety of animal models.
  • 44. Cytolethal Distending Toxins  HdCDT is a complex of three proteins (CdtA, CdtB and CdtC) encoded by three genes that are part of an operon.  Members of this family have been identified in E. coli, Shigella, Salmonella, Campylobacter, Actinobacillus and Helicobacter hepaticus.
  • 45. Toxins acting on intracellular targets: Signal transduction 2 Toxin Organism Activity Consequence Anthrax edema factor (EF) B. anthracis Binding to calmodulin ATP→cAMP conversion cAMP increase Anthrax lethal factor (LF) B. anthracis Cleavage of MAPKK1 and MAPKK2 Cell death, apoptosis Cytotoxin necrotizing factors 1 and 2 (CNF1, 2) E. coli Deamidation of Rho, Rac and Cdc42 Ruffling, stress fiber formation. DNT Bordetella species Transglutaminase, deamidation or polyamination of Rho GTPase Ruffling, stress fiber formation CDT Several species DNA damage, formation of actin stress fibers via activation of RhoA Cell-cycle arrest, cytotoxicity, apoptosis
  • 46. Toxins acting on intracellular targets: Cytoskeleton structure  The cytoskeleton is a cellular structure that consists of a fiber network composed of microfilaments, microtubules, and the intermediate filaments.  It controls a number of essential functions in the eukaryotic cell:  exo- and endocytosis  vesicle transport  cell-cell contact  and mitosis
  • 47. Toxins acting on intracellular targets: Cytoskeleton structure  Most of them do it by modifying the regulatory, small G proteins, such as Ras, Rho, and Cdc42, which control cell shape.
  • 48. Lymphostatin  Lymphostatin is a very recently identified protein in enteropathogenic strains of E. coli  Lymphostatin selectively block the production of interleukin-2, IL-4, IL-5 and γ interferon by human cells and inhibit proliferation of these cells, thus interfering with the cellular immune response.
  • 49. Toxins acting on intracellular targets: Cytoskeleton structure Toxin Organism Activity Toxin C2 and related proteins C. botulinum ADP-ribosylation of monomeric G actin Failure in actin polymerization Lymphostatin E. coli Block of interleukin production Chronic diarrhea Block of interleukin production Chronic diarrhea Iota toxin and related C. perfringens proteins Consequence
  • 50. Toxins acting on intracellular targets: Intracellular trafficking  Vesicle structures are essential in:    receptor-mediated endocytosis and exocytosis One example of exocytic pathway is that involving the release of neurotransmitters
  • 51. Mechanism of action of clostridial neurotoxins (CNT) Synaptosomal-associated protein 25 (SNAP-25)
  • 52. Helicobacter pylori Vacuolating Cytotoxin Vac A  This toxin is responsible for massive growth of vacuoles within epithelial cells.  VacA can insert into membranes forming hexameric, anion-selective pores.
  • 53. Toxins acting on intracellular targets: Intracellular trafficking Toxin Organism Activity Consequence TeNT C. tetanii Cleavage of VAMP/ synaptobrevin Spastic paralysis BoNT-B, D, G and F neurotoxins C. botulinum Cleavage of VAMP/ synaptobrevin Flaccid paralysis BoNT-A, E neurotoxins C. botulinum Cleavage of SNAP-25 Flaccid paralysis BoNT-C neurotoxin C. botulinum Cleavage of syntaxin, SNAP-25 Flaccid paralysis Vacuolating cytotoxin VacA H. pylori Alteration in the endocytic pathway Vacuole formation, apoptosis NAD glycohydrolase S. pyogenes Keratinocyte apoptosis Enhancement of GAS proliferation
  • 54. Toxins injected into eukaryotic cells  These bacteria intoxicate individual eukaryotic cells by using a contact-dependent secretion system to inject or deliver toxic proteins into the cytoplasm of eukaryotic cells.  This is done by using specialized secretion systems that in Gram-negative bacteria are called "type III" or "type IV,“.
  • 55. Class Toxins injected into eukaryotic cells: Acting on Acting on the Mediators of apoptosis: IpaB in Shigella intracellular  cell surface targets Shigella invasion plasmid antigen (Ipa) proteins: IpaA, Immune IpaB, IpaC, IpaD. system Protein synthesis (Superantigens) Only IpaB is required to initiate cell death. Mediators of apoptosis Surface molecules Signal transduction Inositol phosphate metabolism Cell membrane Target  Injected into eukaryotic cells Cytoskeleton structure Cytoskeleton Large pore- forming toxins Intracellular trafficking Signal transduction Small pore- forming toxins RTX toxins Membrane-perturbing toxins
  • 56. Toxins injected into eukaryotic cells: Mediators of apoptosis: SipB in Salmonella  An analog of Shigella invasin IpaB.  In contrast to Shigella, Salmonella does not escape from the phagosome, but it survives and multiplies within the macrophages.  Salmonella virulence genes are encoded by a chromosomal operon named sip containing five genes (sipEBCDA).
  • 57. Toxins injected into eukaryotic cells: Mediators of apoptosis Toxin Organism Activity Consequence IpaB Shigella Binding to ICE Apoptosis SipB Salmonella Cysteine proteases Apoptosis YopP/YopJ Yersinia species Cysteine protease, blocks MAPK and NFkappaB pathways Apoptosis
  • 58. Toxins injected into eukaryotic cells: Inositol phosphate metabolism  SopB: in Salmonella is homologous to the Shigella flexneri lpgD virulence factor.  Both proteins contain two regions of sequence similarities with human inositol polyphosphatases types I and II.
  • 59. Toxins injected into eukaryotic cells: Inositol phosphate metabolism Toxin Organism Activity Consequence SopB Salmonella species Inositol phosphate phosphatase, cytoskeleton rearrangements Increased chloride secretion (diarrhea) IpgD S. flexneri Inositol phosphate phosphatase, cytoskeleton rearrangements Increased chloride secretion (diarrhea)
  • 60. Toxins injected into eukaryotic cells: Signal transduction Toxin Organism Activity Consequence ExoS P. aeruginosa ADP-ribosylation of Ras, Rho GTPase Collapse of cytoskeleton C3 exotoxin C. botulinum ADP-ribosylation of Rho Breakdown of cellular actin stress fibers ADP-ribosylation of Rho Modification of actin cytoskeleton Rac and Cdc42 activation Membrane ruffling, cytoskeletal reorganization, proinflammatory cytokines production EDIN-A, B and C S. aureus SopE S. typhimurium SipA S. typhimurium Rac and Cdc42 activation Membrane ruffling, cytoskeletal reorganization, proinflammatory cytokines production IpaA Shigella species Vinculin binding Depolymerization of actin filaments YopE Yersinia species GAP activity towards RhoA, Rac1 or Cdc42 Cytotoxicity, actin depolymerization YopT Yersinia species Cysteine protease, cleaves RhoA, Rac, and Cdc42 releasing them from the membrane Disruption of actin cytoskeleton VirA Shigella flexneri Inhibition of tubulin polymerization Microtubule destabilization and membrane ruffling
  • 61. Toxins injected into eukaryotic cells: Signal transduction Toxin Organism Activity Consequence YpkA Yersinia species Protein serine/threonine kinase Inhibition of phagocytosis YopH Yersinia species Tyrosine phosphatase Inhibition of phagocytosis Tir E. coli EPEC Receptor for intimin Actin nucleation and pedestalformation CagA H. pylori Tyrosine phosphorylated Cortactin dephosphorylation YopM Yersinia species Interaction with PRK2 and RSK1 kinases Cytotoxicity SptP S. typhimurium Inhibition of the MAP kinase pathway Enhancement of Salmonella capacity to induce TNF-alpha secretion ExoU P. aeruginosa Lysophospholipase A activity Lung injury
  • 62. Toxins with unknown mechanism of action Toxin Organism Activity Consequence Zot V. cholerae ? Modification of intestinal tight junction permeability Hemolysin BL (HBL) B. cereus Hemolytic, dermonecrotic and vascular permeability activities Food poisoning, fluid accumulation and diarrhea BSH L. monocytogenes ? Increased bacterial survival and intestinal colonization
  • 63. Abbreviations SEA-SEI, staphylococcal enterotoxins SHT, Shiga toxin; TSST, toxic shock syndrome toxin PT, pertussis toxin; SPE, streptococcal exotoxin CT, cholera toxin; SSA, streptococcal superantigen LT, heat-labile enterotoxin; SMEZ, streptococcal mitogenic exotoxin z DNT, dermonecrotic toxin; MAM, Mycoplasma arthritidis mitogen CDT, cytolethal distending toxin; YPMa, Y. pseudotuberculosis-derived mitogen TeNT, tetanus neurotoxin; ETA and ETB, exfoliative toxins RTX, repeats in the structural toxin; ColH, collagenase Hly, hemolysin; Nhe, nonhemolytic entertoxin Cry, crystal; PFO, perfringolysin O; BoNT, botulinum neurotoxin; SLO, streptolysin O; Ipa, invasion plasmid antigen;
  • 64. Abbreviations LLO, listeriolysin O; Sip, Salmonella invasion protein; ALO, anthrolisin O; EDIN, epidermal cell differentiation inhibitor; AT, α-toxin; Sop, Salmonella outer protein; PA, protective antigen; Ipg, invasion plasmid gene; DT, diphtheria toxin; Yop, Yersinia outer protein; PAETA, Pseudomonas aeruginosa exotoxin A; GAP, GTPase-activating protein; GAS, group A Streptococcus; Vir, virulence protein; YpkA, Yersinia protein kinase A; Tir, translocated intimin receptor; EPEC, enteropathogenic E. coli; CagA, cytotoxin-associated gene A; SptP, Salmonella protein tyrosine phosphatase; VAMP, vesicle-associated membrane protein; ICE, interleukin-1β-converting enzyme; SNAP, synaptosome-associated protein; MAPKK, mitogen-activated protein kinase ; Zot, zonula. occludens toxin; and BSH, bile salt hydrolase.
  • 66. Substrate Effect DT ADP-ribosyltransferases Toxin Elongation factor EF-2 Cell death PAETA Elongation factor EF-2 Cell death PT Gi, Go and transducin cAMP increase CT Gs, Gt and Golf E. coli LT Clostridium botulinum C2 Actin Failure in actin P. aeruginosa ExoS Ras Collapse of cytoskeleton Clostridium botulinum C3 Rho Breakdown of cellular actin stress fibers
  • 67. Toxin Effect Clostridium difficile toxins A and B Rho/Ras GTPases Breakdown of cytoskeletal structure E. coli CNF1 Glucosyl-transferases Substrate Rho, Rac and CdC42 Stress fiber formation Deamidases Bordetella DNT Metalloproteases Shiga toxin Ribosomal RNA Stop of protein synthesis Bacillus anthracis LF N-Glycosidases Rho, Macrophages Disruption of normal homoeostatic functions Clostridium tetanii TeNT VAMP/synaptobrevin Spastic paralysis C. botulinum BoNTs VAMP/synaptobrevin, SNAP-25 Flaccid paralysis
  • 68. Abbreviations SNAP-25, synaptosome-associated protein of 25 kDa. CNF1, cytotoxin necrotizing factor 1; DNT, dermonecrotic factor; DT, diphtheria toxin; PAETA, Pseudomonas aeruginosa exotoxin A; PT, pertussis toxin; CT, cholera toxin; LT, heat-labile enterotoxin; ExoS, exoenzyme S; LF, lethal factor; TeNT, tetanus neurotoxin; BoNT, botulinum neurotoxin; VAMP, vesicle associated membrane protein;

Editor's Notes

  1. توکسین ها اولین فاکتور ویرولانت باکتریها بودن ک شناخته شدن و همچنین اولین عامل ارتباط بین بیولوژی سلولی و باکتری بودن ک شناخته شد.
  2. حتی آغاز علم میکروبیولوژی هم با مطالعه توکسین ها اتفاق افتاده و تا همین اواخر هم به کمک تکنولوژی های جدید در حال گسترش ارتباطات بین باکتری و میزبانه.
  3. Exotoxin: Easily inactivated by formaldehyde, iodine, and other chemicals to form immunogenic toxoids.
  4. In the first example (figure 34.7a), the exotoxin is produced by bacteria growing in food. When food is consumed, the preformed exotoxin is also consumed. The classical example is staphylococcal food poisoning (see section 39.4) caused solely by the ingestion of preformed enterotoxin. Since the bacteria (Staphylococcus aureus) cannot colonize the gut, they pass through the body without producing any more exotoxin; thus, this type of bacterial disease is self-limiting.In the second example (figure 34.7b), bacteria colonize a mucosal surface but do not invade underlying tissue or enter the bloodstream. The toxin either causes disease locally or enters the bloodstream and is distributed systemically where it can cause disease at distant sites. The classical example here is the disease cholera caused by Vibrio cholerae (see section 39.4). Once the bacteria enter the body, they adhere to the intestinal mucosa where they are not invasive but secrete the cholera toxin, which is an AB exotoxin that catalyzes an ADP– ribosylation similar to that of diphtheria exotoxin (figure 34.5b). As a result, cholera toxin stimulates hypersecretion of water and chloride ions and the patient loses massive quantities of water.The third example of exotoxins in disease pathogenesis occurs when bacteria grow in a wound or abscess (figure 34.7c). The exotoxin causes local tissue damage or kills phagocytes that enter the infected area. A disease of this type is gas gangrene (see section 39.3) in which the exotoxin (-toxin) of Clostridium perfringens causes the tissue destruction in the wound.
  5. Vasodilation:انبساطKupffer:Anatomy a phagocytic liver cell, involved in the breakdown of red blood cells.
  6. نوروتوکسین ها عمدتاً بصورت پیشساز وارد دستگاه گوارش میشن و بعد از فعال شدن یا بطور مستقیم سیستم عصبیو تحت تاثیر قرار میدن، یا بطور غیر مستقیم با اثر روی سلول روده کوچیک باعث بروز علاعمی میشه. مثل انتروتوکسین B استاف اورئوس و توکسین باسیلول سرئوس و توکسین بوتولینوم. انتروتوکسین ها با اثر مستقیم روی مخاط، باعث افزایش ترشح میشن. توکسین کلرا ی نمونه کلاسیک این دسته توکسینهاست. دارای 5 زیر واحد B ک مثل لنگر به غشاء پلاسمایی سلول اپیتلیای متصل میشن و زیر واحد Aرو به داخل منتقل میکنن. سایتوتوکسین ها بطور اختصاصی روی سلول ها هدف عمل میکنن. به نسبت سلول هدف دارای اسم خاص هستن، مثل....معمولاً فعال سایتوتوکسیک وسیعی دارن و باعث مرگ بافت بصورتی ک دلیل اصلی اون مشخص نیست میشن. گاهی به اونا lecithinases یا phospholipasesهم گفته میشه. برخی از سایتوتوکسین ها ک باعث لیزشدن RBCها میشن hemolysinsنام دارن.
  7. three groups of bacterial toxins.Group 1 toxins act either by binding receptors => sending a signal to the cell or by forming pores => perturbing the cell permeability barrier.Group 2 toxins are A/B toxins, binding domain (B subunit)enzymatically active (A subunit).Group 3 toxins are injected directly from the bacterium into the cell by a specialized secretion apparatus (type III or type IV secretion system).
  8. Major histocompatibility complex (MHC) and the T-cell receptor variable domains of T-lymphocytes.اتصال غیرعادی سوپرآنتی ژن باعث میشه 2تا15 درصد سلولهای T فعال بشن. و درنتیجه تکثیر اونا زیاد میشه، سیتوکاینهای زیادی آزاد میشه و منجر به بروز اثرات سایتوتوکسیک میشه.
  9. فقط چهار باکتری دارای سوپر آنتیژن هستن.عمدتاً توسط Staphylococcus and Streptococcus ترشح میشنMaM هم روی Tcellها اثر میزاره و باعش التهاب مزمن میشه و اثر ماتوژنیک و تحریک کننده تقسیم داره
  10. sufficient concentration of an autoinducing peptide (AIPsufficient density of bacteriaAIP binds to transmembrane receptor AgrC outside the cell, turn phosphorylates AgrA, initiating transcription of the agr promoters.P2, which transcribes genes agrA, agrB, agrC, and agrD
  11. بیماریزایی باکتریوئیدس فراژلیس بستگی به توکسین اون با نام فراژلین داره. این توکسین به گیرنده اختصاصی روی سلول اپیتلیال متصل میشه و باعث تحریک تقسیم سلول میشه.
  12. همه دارای خاصیت متالوپروتئاز هستن
  13. این دسته معمولاً در گرم مثبت ها دیده میشه و به توکسین های لایتیک هم مشهوره. با ایجاد حفره در غشائ پلاسمایی باعث خروج ملکول ها و ورود آب به سلول میشن. چون اکثراً از RBC ها برای تشخیص اونا استفاده میشه، به اونا همولایزین هم گفته میشه. ولی در شرایط واقعی همه ی سلولها از حساسیت یکسانی در برابر این توکسین ها برخوردارن.
  14. این توکسین ها عمدتاً توسط گرم + ها ترشح میشن و حدود 20 نوع توکسین هستن. بطور اختصاصی به کلسترول متصل میشن. This class of cytolysins (Fig. 2, panel 2) comprises more than 20 family members, which are generally secreted bytaxonomically diverse species of Gram-positive bacteria and which have the common property of binding selectively tocholesterol on the eukaryotic cell membrane (Alouf and Geoffrey, 1991). Each toxin consists of a single 50- to 80-kDapolypeptide chain, and they are characterized by a pretty remarkable sequence similarity, also suggesting possible similar3D structures.
  15. بطور انتخابی باعث خروج یا ورود مود کمتر از 2 کیلو دالتون میشن. عمدتاً توسط staphylococcal and streptococcal ترشح میشن. ابتدا بصورت یک زیرواحد محلول در آب ترشح میشن بصورت هپتامر درمیان.
  16. بشترشون باعث تغییر نفوذپذیری غشا میشن ولی چندتاشونم باعث القای آپوپتوز در لمفوسیتها میشن.
  17. RTXها توسط گرم منفی ها تولید میشن و بیش از 1000 نوع دارن ک داری انواعی از عملکردهاست.
  18. این دسته دارای دوخصوصیت ویژه هستن: یکی اینکه دارای ی توالی خاص در انتهای خوشونن و اینکه توسط سیستم ترشحی نوع 1 ترشح میشن. نام RTX باین علت به اونا داده شده ک توالی C-terminal اونا دارای تعداد زیادی گلایسینه. این توالی
  19. این توکسینا توسط چهار ژن ساخته میشن ک بخش HlyA دارای خاصیت همولیزینه. بقیه ژنها هم برای انجام تغغیرات پس از ترجمه لازمن.
  20. دارای خاصیت دوقطبی مثل صابون هستن و بطور غیر اختصاصی به غشا متصل میشن. نحوه قرارگرفتنشون طوریه ک با غشا موازی هستن و در غشا ایجاد کانال نمیکنن. نفوذپذیری سلول هدف در ابتدا افزایش پیدا میکنه و نهایتاً در اثر تورم باعث لیزشدن و خروج محتویات سلول میشه. زیر واحد های توکسین در بافر آبی دارای شکل خاصی نیستن ولد در مایعات بدن دارای شکل هلیکس میشن.
  21. یون کلسیم در فعالیت این توکسین ها نقش مهمی داره.
  22. آئروتوکسین هم طی چند مرحله از حالت محلول در آب به شکلی درمیاد ک بتونه در غشا قرار بگیره.
  23. دلتا توکسین استاف ک بصورت ی هلیکسه و کانالیو برای عبور یونها فراهم میکنه.
  24. این توکسینا ک خاصیت حشره کشی دارن به دلتا توکسین ها مشهورن و تعدادی ازونا توسط Bacillus thuringiensis ترشح میشن. اثر این توکسین ها بصورت ایجاد منافذی در لوله گوارش حشرات پدیدار میشه.
  25. Lepidoptera-specific toxin engineer insect-resistant plants
  26. بعضیاشون لیپید 2لایه رو تخریب میکنن و توکسینای B. Thuringiensis هم پتانسیل غشاییو تغییر میده.
  27. عمدتاً دارای ساختار دوقسمتی هستن.
  28. دامین A از لحاظ آنزیماتیک فعاله و مسئول شناخت ساختار هدف در سلول میزبانه. دامین B هم دارای ی ریسپتور غشاییه و مسئول انتقال زیرواحد A.
  29. این توکسین ها قادرن در غلظت های پایین بسرعت باعث مرگ سلولی بشن. فعالیت این توکسین ها باعث غیر فعال شدن دائمی EF-2 میشه.
  30. قدم مهمی در روشن شدن مکانیزم اثر این توکسین ها برداشته شد این بود ک تونستن ساختار 3بعدی توکسینو در حالی ک همراه NAD هستش، تشخیص بدن. و مشخص شد ک حضور NAD در ساختار توکسین اثر زیادی داره طوریکه اگر NAD همراه توکسین نباشه اصلاٌ توکسین قادر به تشخیص EF-2 نیست.
  31. Signal transduction از مکانیزم های بسیار حیاطی برای زنده موندن هر سلوله. در سلولهای یوکاریوتی، پیامی ک به سطح سلول میرسه به دو روش به داخل منتقل میشه. ... ... تجمع این ترکیبات حد واسط باعث بهم خوردن مکانیسم های داخل سلول شده و منجر به مرگ میشود.
  32. The A domain acts on eukaryotic cells by ADP-ribosylating their GTP-binding proteinsThe B domain is a nontoxic oligomer that binds the receptors on the surface of eukaryotic cells and allows the toxicsubunit S1 to reach its intracellular target proteinsrole of many residues of S1 has been tested by site-directed mutagenesis to produce nontoxic mutants of the toxin to be used as vaccines.
  33. A mRNA molecule is said to be monocistronic when it contains the genetic information to translate only a single protein chain (polypeptide). CT کلرا و توکسین LT ایکولای از لحاظ ساختاری و عملکرد بسیار شبیه هم هستن. CT در محیط کشت پخش میشه ولی توکسین LT در غشا خارجی و متصل به LPS باقی میمونه. ژن توکسین CT بوسیله و فاژ فیلامنتوس منتقل میشه ولی ژن توکسین LT روی پلاسمید قرار داره.
  34. انتروتوکسین A کلستریدیوم دیفیسیل و سایتو توکسین B اون، در ایجاد اسهال آنتی بیوتیکی نقش زیادی دارن. ژنهای این توکسین ها در لوکوس PaLoc است که حاوی ژنهای اصلی A و B، و ژنهای کمکی C-D است.
  35. آلفا توکسین مهمترین توکسین کلستریدیوم پرفرینجنس هست و باعث بروز گانگرن میشه. این توکسی در انتشار باکتری نقش مهمی داره. باعث سرکوب ایمنی میزبان و تحریک واکنش های التهابی و تغییر در غلظت کلسیم داخل سلولی میشه. Cel Division Cycle Human CDC42 is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression.
  36. Stress fibers are high order structures in non-muscle cells which consist of actin filaments, crosslinking proteins, and myosin II motors. stress fibers have since been shown to play an important role in cell motility and, providing force for a number of cell functions such as cell adhesionand morphogenesis.[2]
  37. فعالیت اسکلت سلولی توسط پروتئین های G کنترل میشه. Cdc42 ملکولهایی هستن ک کنترل شکل سلولو به عهده دارن. The Ras family is generally responsible for cell proliferation, Rho for cell morphology,
  38. لیمفوستاتین، پروتئینیه ک توسط ایکولای ترشح میشه و بتازگی کشف شده. نقش توکسینی داره و بطور انتخابی تولید انترلوکین های 2 و4 و 5 و اینترفرون گامارو متوقف میکنه، در نتیجه تکثیر سلول های ایمنی متوقف میشه و در ایمنی اختلال ایجاد میشه.
  39. iota-like toxins:C. perfringens iota toxin and C. spiroforme and C. difficile ADP-ribosylating toxins
  40. وزیکول ها از ساختارهای ضروری در فرایند هایی مثل اندوسیتوز به واسطه ریسپتور و اگزوسیتوز هستن. وزیکول ها عمدتاً در شبکه آندوپلاسمی ساخته میشن و پس از تغییراتی در گلژی به سطح سلول میرن.یک نمونه از کاربرد اگزوسیتوز در تنزیم فرایندهای بدن، نقش اون در رهاسازی نوروترنسمیترهاست.
  41. Synaptosomal-associated protein 25 (SNAP-25)SNARE:SNAP REceptorAcetylcholine & neurotransmiters
  42. Vesicle associated membrane proteins (VAMP) are a family of SNARE proteins with similar structure, and are mostly involved in vesicle fusion.
  43. سلولهای میزبانو بصورت تکی مورد هدف قرار میده و با سیستم ترشحی وابسته به اتصال، توکسین به سیتوپلاسم سلول هدف منتقل میشه. This definition failed to explain the pathogenicity of many virulent bacteria such as Salmonella, Shigella and Yersinia, which did not release toxic proteins into the culture supernatant.
  44. فقط شیگلا هایی ک موفق به ترک فاگوزوم میشن میتونن توی میزبان خودشون، آپوپتوز الغا کنن. Ipa توسط سیستم ترشحی نوع 3 به خارج شیگلا فرستاده میشه و بیان ژنهای زیرمجموعه آغاز میشه. بین این زیر واحدها، وجود زیرواحد IpaB برای شروع الغای مرگ سلولی ضروریه. این مکلول روی interleukin-1β ک یکی از افکتورهای مرگ سلولیه اثر میزاره و زمینه گسترش باکتری فراهم میشه.
  45. مشابه اینویزین شیگلاست و برعکس شیگلا ، سالمونلا از فاگوزوم فرار نمیکنه و داخل فاگوزوم زنده میمونه و تکثیر میکنه.
  46. ICE: Caspase 1/interleukin-1 converting enzymeis an enzyme that proteolytically cleaves other proteins, such as the precursor forms of the inflammatory cytokinesinterleukin 1-β and interleukin 18, into active mature peptides.Mitogen-activated protein kinases are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock.NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens
  47. اگزوتوکسینS سودوموناس آئروژینوزا ی توکسینه بادو عملکرد. ADP-ribosyltransferase در دامین سی ترمینال این توکسین قرار داره و بتازگی مسخص شده ک توالی واقع در اِن ترمینال این توکسین باعث گردشدن میزبان میشه. In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton.
  48. Paeta: Pseudomonas aeroginosa exotoxin a