Mechanism of Bacterial Pathogenesis

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Mechanism of Bacterial Pathogenesis
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Virulence 3) Pathogen 4)
Pathogenicity 5) Pathogenicity island 6)
Biofilms
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o Normal flora many of which serve
important functions for their hosts. aid in
the digestion of food, produce vitamins (e.g.,
vitamin K). can protect the host from
colonization with pathogenic microbes.
gastrointestinal (GI) tract, mouth, skin, upper
respiratory tract o Virulent bacteria
promote their growth in the host at the expense
of the host's tissue or organ function.
Disease results from the damage or loss of tissue
or organ function or the development of host
inflammatory responses. o Opportunistic
bacteria take advantage of preexisting
conditions that enhance the susceptibility of the
patient, such as immunosuppression, to grow and
cause more serious disease. Pseudomonas
aeruginosa infects burn victims and the lungs of
patients with cystic fibrosis. patients with
the acquired immune deficiency syndrome (AIDS)
are very susceptible to infection by
intracellularly growing bacteria, such as the
mycobacteria.
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o Infection Multiplication of an infectious
agent within the body Multiplication of
pathogenic bacteria (even if the person is
asymptomatic) is deemed an infection (not in
normal flora) o Pathogen A microorganism
capable of causing disease o Pathogenicity
The ability of an infectious agent to cause
dusease o Virulence The quantitative ability
of an agent to cause disease Virulence
involves invasion and toxigenicity o Virulence
factor enhance the ability of bacteria to
cause diseases o Signs and symptoms of a disease
systemic responses Bacterial strain and
inoculum size - different for different
bacteria o Pathogenicity island components
of virulence factors are often encoded together
- large chromosomal region - coordinated
expression of several genes ex) o SPI-2
pathgenicity island (Salmonella) -
acidic pH (phagocytic vesicle) toxic proteins
o N-acyl homoserine lactone (AHL) -
Pseudomonas Biofilm formation -
Polysaccharide production
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Bacterial Virulence Mechanisms

Adherence Invasion By-products of growth (gas, acid) Toxins Degradative enzymes Cytotoxic proteins Endotoxin Superantigen Induction of excess inflammation Evasion of phagocytic and immune clearance Capsule Resistance to antibiotics Intracellular growth
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How infectious diseases are transmitted

• Direct transmission methods
• Indirect transmission

• Animal ? human
• Yersinia pestis (plaque) - rodent, rodent
  fleas
• Bacillus anthracis (anthrax) - raw hair from
  infected animals
• Environment ? human
• ingestion - Clostridium perfringens
  (gastroenteritis)
• - C. botulinum (botulism)
• Wounds(soil) - C. pefringens (gas gangrene)
• - C. Tetani (tetanus)
• Food contamination
• E. coli
• Seafood, drinking water
• Vibro cholerae
• Human ? human
• Mycobacterium tuberculosis (tuberculosis)
• - Cough and production of aerosols
• Staphylococcus aureus - on hands

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- Emerging and reemerging infectious disease
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Entry into the Human Body
Bacterial Port of Entry
Body surfaces as sites of microbial infection
Route Examples
Ingestion Salmonella sp., Shigella sp., Yersinia enterocolitica, enterotoxigenic Escherichia coli, Vibrio sp., Campylobacter sp., Clostridium botulinum, Bacillus cereus, Listeria sp., Brucella sp.
Inhalation Mycobacterium sp., Nocardia sp., Mycoplasma pneumoniae, Legionella sp., Bordetella, Chlamydia psittaci, Chlamydia pneumoniae, Streptococcus sp.
Trauma Clostridium tetani
Needlestick Staphylococcus aureus, Pseudomonas sp.
Arthropod bite Rickettsia, Ehrlichia, Coxiella, Francisella, and Borrelia spp., Yersinia pestis
Sexual transmission Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum
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Colonization, Adhesion, Invasion
Colonization
o Legionella Lung, cannot tolerate high Temp.
(35 oC) o defect natural defence mechanism, new
portal of entry - cystic fibrosis reduction
of ciliary mucoepithelial function, altered
mucosal secretions - S.
aureus, P. aeruginosa, colonization in lungs
Microbe Adhesin Receptor
Staphylococcus aureus LTA Unknown
Staphylococcus sp. Slime Unknown
Streptococcus, group A LTA-M protein complex Fibronectin
Streptococcus pneumoniae Protein N-acetylhexosamine-gal
Escherichia coli Type 1 fimbriae d-Mannose
  Colonization factor antigen fimbriae GM ganglioside 1
  P fimbriae P blood group glycolipid
Other Enterobacteriaceae Type 1 fimbriae d-Mannose
Neisseria gonorrhoeae Fimbriae GD1 ganglioside
Treponema pallidum P1, P2, P3 Fibronectin
Chlamydia sp. Cell surface lectin N-acetylglucosamine
Mycoplasma pneumoniae Protein P1 Sialic acid
Vibrio cholerae Type 4 pili Fucose and mannose
LTA lipoteichoic acid
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Bacterial biofilms
o aggregate of interactive bacteria attached to a
solid surface (artificial valves, catheters) -
sticky web of polysaccharide - binds the cell
together, to the surface Pseudomonas
aeruginosa airway infection in cystic fibrosis
patients Staphylococcus epidermidis,
Staphylococcus aureus - infection of
central nervous catheters, eye infections
(contact lenses) Dental plaque o Biofilm
matrix protect the bacteria from host defenses
and antibiotics
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Pathogenic Actions of Bacteria
o TISSUE DESTRUCTION
By-products of bacterial growth - production
of acids, gas (fermentation) - substances that
are toxic to tissue Many bacteria release
degradative enzymes - break down tissue -
providing food for the growth of the organisms
- promoting the spread of the bacteria,
especially if blood vessels are involved.
Clostridium perfringens - normal flora of the
GI tract - opportunistic pathogens - infection
in oxygen-depleted tissues and cause gas
gangrene. - produce enzymes (e.g.,
phospholipase C, collagenase , protease,
hyaluronidase ) - several toxins, - acid
and gas from bacterial metabolism, which destroy
the tissue. Staphylococci - hyaluronidase
, fibrinolysin, and lipases. - streptolysins S
and O, hyaluronidase , DNAases, and
streptokinases - facilitate the development of
infection and spread into the tissue
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o TOXINS
Toxins - bacterial products that directly harm
tissue or trigger destructive biologic
activities. - degradative enzymes cause lysis
of cells, - specific receptor-binding proteins
initiate toxic reactions in a specific target
tissue. - cell wall components systemic
response (e.g., fever) by promoting the
inappropriate release of cytokines.
Exotoxins
Endotoxins
1) Excreted by living cell high conc. in
liquid medium 2) Produced by both G() and G(-)
baceria 3) Polypeptides with a MW of
10,000-900,000 4) Relatively unstable toxicity
often destroyed rapidly by heating at above
60oC) 5) Highly antigenic stimulate formation
of high-titer antitoxin. Antitoxin
neutralizes toxin 6) Converted to antigenic,
nontoxic toxoids by formalin, acid, heat etc.
Toxoids are used to immunize (eg, tetanus
toxoid) 7) Highly toxic fatal to animals in mg
quantities or less 8) Usually bind to specific
receptors on cells 9) Usually do not produce
fever in the host 10) Frequently controlled by
extrachromosomal genes (eg, plasmids)

• Integral part of the cell wall of G(-) bacteria.
• Released on bacterial death and in part during
  growth
• 2) Found only in G(-) bacteria
• 3) LPS complexes. Lipid A portion probably
• responsible for toxicity
• 4) Relatively stable withstand heating at above
  60oC for
• hours without loss of toxicity
• 5) Weakly immunogenic
• 6) Not converted to toxoids
• 7) Moderately toxic fatal for animals in 10-100
  mg quantities
• 8) Specific receptors not found on cells (????)
• 9) Usually produce fever in the host by release
  of IL-1

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o Enterotoxins
protein toxin released by a microorganism in
the intestine chromosomally encoded exotoxins
often heat stable, low MW, water soluble
cytotoxic and kill cells by altering the apical
membrane permeability of the mucosal
(epithelial) cells of the intestine wall
increased cAMP, increased calcium ion conc.
intracellularlly diarrhea o Escherichia coli
O157H7 o Clostridium perfringens o Vibrio
chorea o Staphylococcus aureus o Yersinia
enterocolitica o Shigella dysenteriae
o EXOTOXINS

• Exotoxins
• proteins - produced by gram-positive or
  gram-negative bacteria
• cytolytic enzymes
• receptor-binding proteins
• alter a function or kill the cell.
• In many cases, the toxin gene is encoded on a
  plasmid
• - tetanus toxin of C. tetani,
• - LT(heat-labile) and ST (heat-stable)toxins
  of enterotoxigenic E. coli
• lysogenic phage (Corynebacterium diphtheriae
  and C. botulinum.
• cytolytic enzyme, a-toxin (phospholipase C)
  produced by C. perfringens,
• - breaks down sphingomyelin and other
  membrane phospholipids, resulting in cell lysis

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o Mode of action of dimeric A-B exotoxins
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o Superantigen

• TCR-MHC interaction without specific antigen
• Cytokine storm IL-1, TNF, IL-12
• Life-threatening autoimmune-like responses
• Toxic shock syndrome toxin of S. aureus
• Staphylococcal enterotoxins
• Erythrogenic A or C of S. pyrogenes

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o ENDOTOXIN AND OTHER CELL WALL COMPONENTS

• o Lipopolysaccharide (LPS) endotoxin.
• gram-negative bacteria
• Firmly bound to the cell surface
• released only when the cells are lysed
• powerful activator of acute-phase and
  inflammatory reactions
• The lipid A portion of LPS is responsible for
  endotoxin activity. - Endotoxin is not the same
  as exotoxin
• only gram-negative bacteria make endotoxin
• o Endotoxin-like pyrogenic acute-phase responses
• Peptidoglycan
• Teichoic
• lipoteichoic acids, are released, and these
  stimulate.

Endotoxin-Mediated Toxicity

Fever Leukopenia, followed by leukocytosis Activation of complement Thrombocytopenia Disseminated intravascular coagulation Decreased peripheral circulation and perfusion to major organs Shock Death
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Immunity to bacteria
Mechanisms of immunity are related to bacterial
surface structure

• Four main types of bacterial cell wall -
  Gram-positive bacteria, -Gram-negative bacteria
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  - Mycobacteria, -Spirochaetes
• Outer lipid bilayer of G(-) bacteria
• - Lyse membrane complement cytotoxic cells
• Other types of bacteria
• - Phagocytosis
• Outer surface of the bacterium - Fimbriae,
  fragellae
• covered by a protective capsule
• phagocytes, complement ?? ?? ? Targets for the
  antibody response

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Mechanism of immunity are related to bacterial
mechanisms of pathogenicity

• Patterns of pathogenicity
• Toxicity without invasiveness Corynebacterium
  diphtheriae, Vibrio cholerae
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  Pathogenicity depends on toxin production
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  Neutralizing antibody
• -Invasiveness without toxicity Pathogenicity
  does not depends on single toxin
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  Immunity requires killing
• -Most bacteria are intermediate between these
  extremes

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Mechanism for escaping host defense
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Pathogenic bacteria may avoid the effects of
antibody
- Neisseria gonorrhoeae
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Pathogenic bacteria can avoid the detrimental
effects of complement
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