TOXIGENESIS
Two types of bacterial toxins
• lipopolysaccharides, which are associated
with the cell walls of Gram-negative bacteria.
• proteins, which may be released into the
extracellular environment of pathogenic
bacteria.
Endotoxins
Endotoxins are:
 Toxic to most mammals.
 They are strong antigens but they seldom elicit immune responses
which give full protection to the host against secondary challenge with
the endotoxin.
 They cannot be toxoided.
 Endotoxins released from multiplying or disintegrating bacteria
significantly contribute to the symptoms of Gram-negative bacteremia
and septicemia, and therefore represent important pathogenic factors
in Gram-negative infections.
 All endotoxins produce the same range of biological effects in the host,
causes a wide spectrum of nonspecific pathophysiological reactions
related to inflammation such as:
Fever ,changes in white blood cell counts ,disseminated intravascular
coagulation ,hypotension ,shock ,lethality
Bacterial Endotoxins
• Endotoxins
– Host cell receptors (TLR) bind to
components of pathogen
– Pathogen associated molecular
patterns PAMPS
• LPS – gram - cell walls
• Flagella
• Lipoteichoic acid – gram + cell walls
– Signal transduction pathways begin to
illicit a cellular response
• Production of cytokines
Inflammation
Opsonization
MAC
Exotoxins
-several types and specificities.
-They usually have two general
functions, which can often be
uncoupled: the ability to bind to a
host cell receptor, and enzymatic
activity. For example, cholera toxin
,labile toxin, and many others have
five binding (B) subunits coupled to
the active enzymatic subunit (A).
Several vaccines are made from the B
subunits without the catalytic subunit,
ensuring no toxin activity. The B
subunits bind to host cell molecules
such as carbohydrates (for example,
cholera binds the GM1 ganglioside, a
glycolipid on the intestinal surfaces).
Following binding, the A subunit then
enters the cell, which is facilitated by
the B subunits.
Bacterial Exotoxins
Also see page
399 of textbook
• Exotoxins
– Initial location outside cells
– Transported into host cells
– Alter host cell physiology
and metabolism
– Typical A – B toxins
AB toxin enters cells via:
1) Receptor mediated endocytosis
2) Fusion of vesicle with lysosome
3) Acid environment of lysosome
reduces disulfide bonds and
releases A into cell
4) A has various cellular activities
Mechanism of Action
of cholerae toxin
• Normally
– Adenylate cyclase (AC) enzyme
which makes cAMP
– Epithelial cells secrete digestive
fluid (HCO3-) in response to small
increases in cAMP levels
• cholerae exotoxin
–
–
–
–
Over activation of AC
ADP ribosylation of AC
Causes 100X increase in cAMP
Causes huge amounts of water
and Cl- to leave via channels
Pyrogenic exotoxins
They " produced by Staphylococcus aureus and
Streptococcus pyogenes have been designated as
superantigens. They represent a family of
molecules with the ability to elicit massive
activation of the immune system. These proteins
share the ability to to elicit massive activation of
the immune system. These proteins share the
ability to stimulate T cell proliferation by
interaction with Class II MHC molecules on
APCs and specific V beta chains of the T cell
receptor. The important feature of this
interaction is the resultant production of IL-1,
TNF, and other lymphokines which appear to be
the principal mediators of disease processes
associated with these toxins.
CHARACTERISTICS OF BACTERIAL
ENDOTOXINS AND EXOTOXINS
Properities
Chemical nature
Relationship to cell
Denaturated by boiling
Antigenic
Form toxoid
Potency
Specifity
Enzymatic activity
Pyrogenicity
Endotoxin
Exotoxin
Lipopolysaccharide
Protein
Part of outer membrane
Extracellular, diffusible
No
Usually
Yes
Yes
No
Yes
Relatively low (>100ug)
Relatively high (1 ug)
Low degree
High degree
No
Usually
Yes
Occasionally
Pathogenicity Islands
Pathogenicity Islands (PAI) are a distinct class of genomic
islands which are acquired by gene transfer. They are
incorporated in the genome of pathogenic bacteria but are
usually absent from non-pathogenic organisms of the same or
closely related species. They usually occupy genes which
contribute to virulence of the pathogen. Typical examples are
adhesins, toxins, iron uptake systems, invasins, etc.
One species of bacteria may have more than one pathogenicity
island. For example, in Salmonella, five pathogenicity islands
have been identified. They are found mainly in Gram-negative
bacteria, but have been shown in a few Gram-positives.
Pathogenicity islands may be located on the bacterial
chromosome or may be a part of a plasmid. Pathogenicity
islands play a pivotal role in the virulence of bacterial
pathogens of human .
Transmission of infection
• Specific bacterial species (or strains within a
species) initiate infection after being
transmitted by different routes to specific sites
in the human body. For example:• Bacteria are transmitted in airborne droplets to
the respiratory tract
• By ingestion of food or water
• By sexual contact.
The role of bacterial biofilms
• A biofilm is an aggregate of microorganisms in which cells
are stuck to each other and/or to a surface. These adherent
cells are frequently embedded within a self-produced matrix of
extracellular polymeric substance (EPS). Biofilm EPS, which
is also referred to as "slime," is a polymeric of DNA, proteins
and polysaccharides. Biofilms may form on living or nonliving surfaces, and represent a prevalent mode of microbial
life in natural, industrial and hospital settings.
• Biofilms have been found to be involved in a wide variety of
microbial infections in the body, by one estimate 80% of all
infections. Infectious processes in which biofilms have been
implicated include common problems such as urinary tract
infections, catheter infections, middle-ear infections, formation
of dental plaque, gingivitis, coating contact lenses.
Polymicrobic biofilm grown on a stainless steel surface in a
laboratory