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Chapter 15
Microbial Mechanisms
of Pathogenicity
Microbial Mechanisms of
Pathogenicity
• Pathogenicity: the ability to cause disease
• Virulence: the degree or extent of
pathogenicity
• Disease is caused by the microbe overpowering
the host’s defense (immune response)
– Due to microbes directly damages host tissue
– Due to accumulation of microbial waste products
How Microorganisms Enter a Host
• Portals of entry: the avenue by which a
pathogen gains access to the body
– Mucous membranes
penetrate membrane
lining; Most pathogens enter through the mucous
membranes of the gastrointestinal and respiratory
tracts
• respiratory tract: by inhalation (easiest and most
commonly used route)
• gastrointestinal tract: by food, water and
contaminated fingers
• genitourinary tract: sexually
• conjunctiva: birth canal, contact lenses, hands/fingers
How Microorganisms Enter a Host
– Skin
through hair follicles and sweat gland
ducts; intact skin is the first line of defense; most
microorganisms cannot penetrate intact skin
– Parenteral route: direct deposition into tissues
beneath the skin and mucous membranes by
punctures, injections, bites, cuts, wounds, surgery
and splitting
• Many pathogens have a preferred portal of
entry
entry through other portal may not
cause disease
Numbers of invading microbes
• ID50: Infectious dose for 50% of the test
population
– Used to compare the relative virulence of a
microbe under experimental conditions
– e.g. Bacillus anthracis (can cause infection via
3 different portals of entry
Portal of entry
Skin (cutaneous anthrax)
ID50
10-50 endospores
Inhalation (inhalation anthrax)
10,000-20,000 endospores
Ingestion (gastrointestinal anthrax) 250,000-1,000,000 endospores
Numbers of invading microbes
• LD50: Lethal dose (of a toxin) for 50% of the
test population
– Used to express the potency of a toxin
– e.g. LD50 in mice
botulinum toxin
0.03 ng/kg
Shiga toxin
250 ng/kg
staphylococcal enterotoxin 1,350 ng/kg
Adherence (Attachment)
• Adhesins/ligands bind to complementary surface
receptors on host cells
• Host cell receptors are typically sugars (e.g.
mannose)
• Majority of adhesins on the microorganisms are
glycoproteins or lipoproteins
– Glycocalyx
– Fimbriae
– M protein
Streptococcus mutans
Escherichia coli
Streptococcus pyogenes
Adherence (Attachment)
– Opa protein
– Tapered end
Neisseria gonorrhoeae
Treponema pallidum
• Biofilms: a microbial community that
usually forms a slime layer on a surface
– Mass of microbes attach to living and nonliving
surfaces by their extracellular products (e.g.
glycocalyx)
– e.g. Dental plaque, scum on shower doors,
contact lenses, heart valves, medical catheters
– Resist disinfectants and antibiotics
How Bacterial Pathogens Penetrate
Host Defenses
• Capsule
increases the virulence by
resisting the phagocytosis
– e.g. Streptococcus pneumoniae, Klebsiella
pneumoniae, Haemophilus influenzae, and
Bacillus anthracis
– Host’s defense: antibodies produced against
capsules allows encapsulated bacteria to be
destroyed by phagocytosis
How Bacterial Pathogens Penetrate
Host Defenses
• M proteins (on cell surface and fimbriae)
mediates attachment and helps resist
phagocytosis
– Host’s defense: antibodies against M proteins
• Waxes in the cell wall of Mycobacterium
tuberculosis
resist digestion by
phagocytes; bacteria can even multiply
inside phagocytes
How Bacterial Pathogens Penetrate
Host Defenses
• Extracellular (exoenzymes) enzymes aid
virulence
– Coagulase
coagulate (clot) fibrinogen in
blood; fibrin clot may protect the bacterium from
phagocytosis and isolate bacteria from other
defenses of the host
– Kinases
digest/dissolve fibrin clots; allows
bacteria to spread from a localized area
How Bacterial Pathogens Penetrate
Host Defenses
– Hyaluronidase
hydrolyses hyaluronic acid;
cause the tissue blackening of infected wounds and
allows bacteria to spread from the initial site of
infection
– Collagenase
hydrolyzes collagen; helps bacteria
to spread
– IgA proteases
destroy IgA antibodies; remove
protection on mucosal surfaces
How Bacterial Pathogens Penetrate
Host Defenses
• Antigenic variation: alter surface proteins
(antigens) to escape antibodies (can inactivate
or destroy antigens)
– activating alternative genes (e.g. Opa protein)
• Penetration into the host cell cytoskeleton
– Use host’s cytoskeleton (actin) to move through
the host cytoplasm and between host cells (e.g.
Shigella species and Listeria species)
– Invasins: cause formation of an actin basket
around Salmonella and move bacteria into the cell
Penetration into the Host Cell
Figure 15.2
How Bacterial Pathogens Damage
Host Cells
• If phagocytes can eliminate invading
microorganisms, no further damage is done.
• If pathogens overcome the host defense
damage to the host cells
– Use the host’s nutrients
– Cause direct damage at the site of infection
– Produce toxins (cause damage in other parts of
the body)
– Induce hypersensitivity reactions
Using the host’s nutrient
• Iron (required for most pathogens’ growth)
– Some produce siderophores
secreted by
bacteria to take iron from host iron-transport
proteins
– Some have receptors that bind directly to irontransport proteins and hemoglobin
– Some produce toxins
kill the host cells to
obtain iron from dead host cells
Direct damage
• Pathogens cause damage by rupturing the
host cells as they metabolize and multiply
inside cells
– Use host cell for nutrients and produce waste
– As the host cells rupture, pathogens are released
and free to spread infections
• Most damage is done by production of
toxins
Production of toxins
• Toxin: poisonous substances that contribute to
pathogenicity
– Exotoxins (many are encoded by plasmids or
lysogenic conversion) and endotoxins
• Toxigenicity: ability to produce a toxin
• Toxemia : presence of toxin in the host's blood
• Toxoid: inactivated toxin used in a vaccine
(e.g. diphtheria and tetanus vaccine)
• Antitoxin: antibodies against a specific toxin;
provide immunity to exotoxins
Exotoxins
• Proteins (many are
enzymes
can be used
over and over again)
• Most of the genes are
carried on bacterial
plasmids or phages
• Soluble in body fluids
rapidly diffuse and
transport throughout the
body
Figure 15.4a
Exotoxin
• Only need minute amount to cause diseases;
among the most lethal substances known
– Signs and symptoms of the disease is caused by
exotoxin, not by bacteria
• Can induce formation of antitoxins
• Three principal types of exotoxins (based on
structure and function)
– A-B toxins or type III toxins
– Membrane-disrupting toxins or type II toxins
– superantigens or type I toxins
Exotoxins
• A-B toxins (type
III toxins)
– Majority of
exotoxins in this
category
– 2 parts: A is the
active (enzyme)
component & B is
the binding
component
Figure 15.5
Exotoxins
• Membrane-disrupting toxins or type II toxins
– Lyse host’s cells by:
• Making protein channels in the plasma membrane (e.g.
hemolysins and leukocidins)
– hemolysins: form protein channels to destroy erythrocyte
(staphylococci and streptococci)
• Disrupting phospholipid bilayer
– Contribute to virulence by killing host immune
cells (phagocytic cells) and aid bacteria to escape
from phagosomes into the host’s cytoplasm
• e.g. Leukocidins (kill phagocytic leukocytes and
macrophages by forming protein channels)
Exotoxins
• Superantigens or type I toxins
– Bacterial proteins (e.g. staphylococcus toxins
which cause food poisoning & toxic shock
syndrome)
– Cause an intense immune response to release
cytokines from host T cells (nonspecific
stimulation of T cells causing proliferation and
release massive amount of cytokines)
– Excessively high levels of cytokines (small protein
hormones) enter the bloodstream to cause fever,
nausea, vomiting, diarrhea, shock, and even death
Exotoxins
• Neurotoxins: attaches to nerve cells and
interferes with normal nerve impulse
conduction
• Cytotoxins: attaches to wide variety of cells and
either kills host cells or alters their function
– Erythrogenic toxins: damage the plasma membrane
of blood capillaries under the skin and produce a
red skin rash (e.g. Streptococcus pyogenes)
• Enterotoxins: attaches to the lining of the
gastrointestinal tract and cause gastroenteritis
Exotoxins
Exotoxin
Lysogenic
conversion
A-B toxin. Inhibits protein
synthesis.
+
• Streptococcus pyogenes
Membrane-disrupting.
Erythrogenic.
+
• Clostridium botulinum
A-B toxin. Neurotoxin
+
• C. tetani
A-B toxin. Neurotoxin
• Vibrio cholerae
A-B toxin. Enterotoxin
• Corynebacterium
diphtheriae
• Staphylococcus aureus
Superantigen. Enterotoxin.
+
Endotoxin
= Lipid A
Figure 15.4b
Bacterial Cell Wall
Fig. 4.13 b & c
Endotoxins
• Lipopolysaccharides (Lipid A portion)
• Released when gram-negative bacteria die and
their cell walls lyse
– Antibiotics can lyse the bacterial cells to release
endotoxins
– Endotoxins also released during bacterial
replication
• Salmonella typhi, Proteus spp., and Neisseria
miningitidis
Endotoxins
• All endotoxins produce the same sings and
symptoms; however not to the same degree
–
–
–
–
Chills, fever, weakness, generalized aches
In some cases, shock and even death
Can also cause miscarriage
Activate blood-clotting proteins
cut off or
reduce blood supply
death of tissues =
disseminated intravascular clotting
• Stimulate macrophages to release cytokines
in very high concentrations (toxic level)
– IL-1 and TNF
Endotoxins
• Fever (pyrogenic response)
Figure 15.6
– Aspiring & acetaminophen reduce fever by blocking
the synthesis of prostaglandins
Endotoxins
• Shock: any life-threatening loss of blood
pressure
– Septic shock: shock caused by bacteria
– Endotoxic shock: shock caused by gram-negatives
• Release of tumor necrosis factor (TNF) or
cachectin by phagocytes (after ingesting gramnegative bacteria) into the bloodstream
TNF damage blood capillaries
drop in
blood pressure
septic shock
Endotoxins
• Do not induce effective antitoxins formation
– Antibodies are produced, but tend not to
counter the effect of the toxin
• Endotoxins are more stable at high heat than
exotoxins
• Limulus amoebocyte lysate (LAL) assay
used to detect presence of endotoxin in
drugs, medical devices, and body fluids
Plasmids, lysogeny, and
pathogenicity
• Plasmids carry genes for antibiotic resistance
(R factors) & information for pathogenicity
(virulence factors)
– Encode for toxins, capsules, and fimbriae
• Prophage (lysogeny)  lysogenic conversion
– Immune to infection by the same type of phage
– Increase pathogenicity (genes for toxins, capsules)
– Increase number of pathogenic bacteria
(horizontal transfer)
Pathogenic Properties of Viruses
• Mechanism for evading host defenses
– Penetrate and grow inside host cells to evade
the reach of components of the immune system
– Gain access to the potential host cells using
attachment sites (on virus) specific to receptors
on the potential host cells
• Sometimes, attachment sites mimic substances
useful to the host cells
– Hide attachment sites from the immune
response + attack components of the immune
system directly (e.g. HIV virus)
Pathogenic Properties of Viruses
• Cytopathic effects (CPE) of viruses: visible
effects of viral infection
– Cytocidal effects: result in cell death
– Noncytocidal effects: result in cell damage but
not cell death
– Stop synthesis of macromolecules in the host;
stop mitosis; loss of contact inhibition
– Formation of inclusion bodies; syncytium
– Induce production of interferons in infected cells;
antigenic changes on the surface of the infected
cells; chromosomal changes in the infected cells;
transformation
Cytopathic Effects of Viruses
Table 15.4
Pathogenic Properties of Fungi
• No well-defined set of virulence factors
• Fungal waste products (toxins) may cause
symptoms
– Tichothecene toxins inhibit protein synthesis (e.g.
Fusarium)
– Ergot toxin = hallucinogen (e.g. Claviceps)
– Aflatoxin (e.g. Aspergillus) is carcinogenic
– Mycotoxins (neurotoxins such as phalloidin &
amanitin, produced by Amanita) may be lethal if
ingested
Pathogenic Properties of Fungi
• Chronic infections provoke an allergic
response
• Some have Virulence factors such as
proteases (e.g. Candida, Trichophyton)
– Allow attachment of the fungi by modifying host
cell membranes
• Capsule prevents phagocytosis (e.g.
Cryptococcus)
• Decrease synthesis of receptors for antifungal
drugs & become resistant to the drugs
Pathogenic Properties of Protozoa
• Presence of protozoa & protozoan waste
products may cause symptoms
• Avoid host defenses by
– Growing in phagocytes (e.g. Plasmodium &
Toxoplasma)
– Antigenic variation (e.g. Trypanosoma)
• Attach and digest the host cells and tissue fluids
(e.g. Giardia)
Pathogenic Properties of
Helminths and Algae
• Presence of parasite (helminth) interferes with
host function
• Parasite's metabolic waste can cause
symptoms
• Use host tissues for their growth  cellular
damage (cause symptoms)
• Few species of algae (dinoflagellates) produce
neurotoxins
– e.g. Saxitoxin cause paralytic shellfish poisoning
Portals of Exit
• Microbes leave the body through specific
routes to spread infections  generally a
microbe uses the same portal for entry and exit
– Respiratory tract (most common portal of exit) via
mouth and nose by coughing or sneezing
– Gastrointestinal tract (most common portal of exit)
via feces or saliva
– Genitourinary tract via secretions from the penis
and vagina (for sexually transmitted diseases) or
urine
Portals of Exit
– Skin or wound infections via shedding, contact,
or drainage from wounds
– Infected blood via biting arthropods,
needles/syringes
Mechanisms of Pathogenicity
Figure 15.9
Chapter Review
Figure 15.9
Chapter Review
1. Know different portals of entry and exit,
and how they enter or leave a host
–
Generally a microbe uses the same portal for
entry and exit
•
–
respiratory and gastrointestinal tracts = most
common portal of entry and exit
Mucous membranes
•
•
•
respiratory tract – enter by inhalation; exit by
mouth and nose through coughing or sneezing
gastrointestinal tract – enter by food, water, and
contaminated fingers; exit by feces or saliva
genitourinary tract – transmitted sexually; exit
through secretions from the penis and vagina (for
STDs) or urine
Chapter Review
– Skin  cannot penetrate unbroken skin; enter through
hair follicles and sweat gland ducts; exit through
shedding, contact (e.g. sweat)
– Parenteral route: direct deposition into tissues beneath
the skin and mucous membranes by punctures,
injections, bites, cuts, wounds, surgery and splitting; if
there is wound infection, exit through drainage from
wounds, blood-borne pathogen exit through biting
arthropods or needles/syringes
– Many pathogens have a preferred portal of entry; if
enter through different portal, may not cause disease
Chapter Review
2. Know how pathogens adhere or attach to a
susceptible host
– Pathogens use adhesins or ligands to bind to
complementary surface receptors on host cells
– E.g. of adhesins/ligands: glycocalyx
(Streptococcus mutans); fimbriae (Escherichia
coli); M protein (Streptococcus pyogenes); Opa
protein (Neisseria gonorrhoeae)
– Pathogens can also use biofilms to adhere (mass
of bacteria secrete glycocalyx) to living and
nonliving surface; biofilms resist disinfectants
and antibiotics
Chapter Review
•
•
Biofilms: a microbial community that usually
forms a slime layer on a surface
e.g. Dental plaque, scum on shower doors, contact
lenses, heart valves, medical catheters
3. Know how pathogens penetrate or evade
host defenses
–
Capsule formation: resist phagocytosys
host antibodies produced against capsules
allow encapsulated bacteria to be destroyed
by phagocytosis
Chapter Review
– Cell wall components (contain chemical
substances) contribute to virulence
• M proteins: mediates attachment and helps resist
phagocytosis
antibodies produced against M
protein by host allows bacteria to be destroyed
• Waxes in the cell wall of Mycobacterium: resist
digestion by phagocytes; bacteria can even multiply
inside phagocytes
tend to become a chronic
disease
– Extracellular enzymes (exoenzymes) aid in
virulence
• protect the bacterium by forming a protective clot to
avoid phagocytosis and other host’s defenses
Coagulase
Chapter Review
• Allows bacterium to spread from the initial site of
infection
kinases, hyaluronidase & collagenase
• Remove protection on mucosal surfaces
IgA
proteases
– Antigenic variation: escape inactivation or
destruction by host’s antibodies
– Penetration into the host cell cytoskeleton
• Invasins (Salmonella bacteria) to carry bacteria into
the cell
• Use host’s cytoskeleton to move through the host
cytoplasm and between host cells (Shigella species
and Listeria species)
Chapter Review
4. Know how bacteria pathogens can damage
host cells
– Cause direct damage at the site of infection by
rupturing the host cells as they metabolize and
multiply
Release from the host allows spread
of infections
– Production of toxins cause the most damage to a
host (cause damage in other parts of the body)
• Many of the exotoxins (proteins; many are enzymes) are
encoded by plasmids or lysogenic conversion
• Endotoxins are part of gram-negative cell wall (Lipid A)
Chapter Review
– Carrying plasmids allow bacteria to become
antibiotic resistant; increase pathogenicity
(carry virulence factors such as genes for
toxins, capsule, and fimbriae)
– Lysogenic conversion: prophage carry genes
for toxins & capsules to increase pathogenicity;
increase number of pathogenic bacteria
(horizontal transfer)
Chapter Review
5. Know pathogenic properties of viruses
– Viruses can cause cytocidal effects (kill host cells)
or noncytocidal effects (result in cell damage, not
cell death)
– Mechanisms for evading host defenses
• Evade the host’s immune response by growing
intracellularly
• Gain access to the host cells using attachment sites (on
virus) to bind to specific receptors (on hosts)
• Hide attachment sites (on virus) from the immune
response or attack components of the immune system
directly
Chapter Review
6. Know pathogenic properties of fungi,
protozoa, helminths, and algae
– fungi
toxins (e.g. aflatoxin & mycotoxins);
capsules; chronic infections cause allergic
response; some become resistant to antifungal
drugs by decreasing synthesis of receptors for the
drugs
– Protozoa
avoid host defense by growing
inside phagocytes; antigenic variation; damage to
host tissues; metabolic waste
Chapter Review
– Helminth
metabolic waste; cellular damage
(tissue damage)
– Algae (dinoflagellates)
neurotoxins
7. Know these terms: pathogenicity, virulence,
toxigenicity, toxoid, antitoxin, septic shock