Microbial Mechanisms of
Pathogenicity
Prof. Khaled H. Abu-Elteen
Infection and Disease
A. Definitions
B. Generalized Stages of Infection
C. Virulence Factors and Toxins
A. Definitions

Disease and Infectious Disease
• Disease
• Any deviation from a condition of good
health and well-being
• Infectious Disease
 A disease condition caused by the presence
or growth of infectious microorganisms or
parasites
A. Definitions

Pathogenicity and Virulence
• Pathogenicity
• The ability of a microbe to cause disease
• This term is often used to describe or compare
species
• Virulence
• The degree of pathogenicity in a microorganism
• This term is often used to describe or compare
strains within a species
Definitions

Acute infection vs. chronic infection
• Acute Infection
• An infection characterized by sudden onset,
rapid progression, and often with severe
symptoms
• Chronic Infection
• An infection characterized by delayed onset
and slow progression
Definitions

Primary infection vs. secondary infection
• Primary Infection
• An infection that develops in an otherwise
healthy individual
• Secondary Infection
• An infection that develops in an individual
who is already infected with a different
pathogen
Definitions

Localized infection vs. systemic infection
• Localized Infection
• An infection that is restricted to a specific
location or region within the body of the host
• Systemic Infection
• An infection that has spread to several
regions or areas in the body of the host
Definitions

Clinical infection vs. subclinical infection
• Clinical Infection
• An infection with obvious observable or
detectable symptoms
• Subclinical Infection
• An infection with few or no obvious
symptoms
Definitions

Opportunistic infection
• An infection caused by microorganisms that are
commonly found in the host’s environment.
This term is often used to refer to infections
caused by organisms in the normal flora.
Definitions

The suffix “-emia”
• A suffix meaning “presence of an infectious agent”
• Bacteremia = Presence of infectious bacteria
• Viremia = Presence of infectious virus
• Fungemia = Presence of infectious fungus
• Septicemia = Presence of an infectious agent in
the bloodstream
Definitions

The suffix “-itis”
• A suffix meaning “inflammation of”
• Examples:
– Pharyngitis = Inflammation of the pharynx
– Endocarditis = Inflammation of the heart
chambers
– Gastroenteritis = Inflammation of the
gastointestinal tract
Definitions

Epidemiology
• The study of the transmission of disease

Communicable Disease
• A disease that can be transmitted from one
individual to another

Noncommunicable Disease
• A disease that is not transmitted from one
individual to another
Definitions

Endemic Disease
• A disease condition that is normally found in a
certain percentage of a population

Epidemic Disease
• A disease condition present in a greater than
usual percentage of a specific population

Pandemic Disease
• An epidemic affecting a large geographical
area; often on a global scale
Definitions

Reservoir of Infection
• The source of an infectious agent

Carrier
• An individual who carries an infectious agent
without manifesting symptoms, yet who can
transmit the agent to another individual

Fomites
• Any inanimate object capable of being an
intermediate in the indirect transmission of an
infectious agent
Definitions
• Animal Vectors
• An animal (nonhuman) that can transmit an
infectious agent to humans
• Two types: mechanical and biological
• Mechanical animal vectors: The infectious agent is
physically transmitted by the animal vector, but the agent
does not incubate or grow in the animal; e.g, the
transmission of bacteria sticking to the feet of flies
• Biological animal vectors: The infectious agent must
incubate in the animal host as part of the agent’s
developmental cycle; e.g, the transmission of malaria
by infected mosquitoes
Definitions

Direct Mechanisms of Disease Transmission
• Directly From Person to Person
• Examples:
Direct Skin Contact
Airborne (Aerosols)
Definitions

Indirect Mechanisms of Disease Transmission
• Examples:
Food & Waterborne Transmission
Fomites
Animal Vectors
Pathogenicity - ability to cause disease
Virulence - degree of pathogenicity


Many properties that determine a microbe’s
pathogenicity or virulence are unclear or
unknown
But, when a microbe overpowers the hosts
defenses, infectious disease results!
Molecular Determinants of Pathogenicity
Attachment
to host
tissues
Production
and delivery
of various
factors
Replication
and evasion
of immunity
Damage to
host tissues
Microbial Mechanisms of Pathogenicity:
How Microorganisms Cause Disease
Portals of Entry

1. Mucus Membranes

2. Skin

3. Parentarel
1. Mucus Membranes

A. Respiratory Tract
• microbes inhaled into
mouth or nose in
droplets of moisture or
dust particles
• Easiest and most
frequently traveled
portal of entry
Common Diseases contracted via
the Respiratory Tract







Common cold
Flu
Tuberculosis
Whooping cough
Pneumonia
Measles
Diphtheria
Mucus Membranes

B. Gastrointestinal Tract
• microbes gain entrance thru
contaminated food & water
or fingers & hands
• most microbes that enter the
G.I. Tract are destroyed by
HCL & enzymes of stomach
or bile & enzymes of small
intestine
Common diseases contracted via
the G.I. Tract
 Salmonellosis
• Salmonella sp.

Shigellosis
• Shigella sp.

Cholera
• Vibrio cholorea

Ulcers
• Helicobacter pylori

Clostridium botulinum
Botulism
• Clostridium botulinum
Fecal - Oral Diseases

These pathogens enter the G.I. Tract at one
end and exit at the other end.

Spread by contaminated hands & fingers or
contaminated food & water
Poor personal hygiene.

Mucus Membranes of the Genitourinary System - STD’s
Gonorrhea
Neisseria gonorrhoeae
Syphilis
Treponema pallidum
Chlamydia
Chlamydia trachomatis
HIV
Herpes Simplex II
Mucus Membranes

D. Conjunctiva –
• mucus membranes that
cover the eyeball and lines
the eyelid

Trachoma
• Chlamydia trachomatis
2nd Portal of Entry: Skin

Skin - the largest organ of the body. When
unbroken is an effective barrier for most
microorganisms.

Some microbes can gain entrance through
openings in the skin: hair follicles and sweat
glands, wound …etc
3rd Portal of Entry: Parentarel





Microorganisms are deposited into the
tissues below the skin or mucus membranes
Punctures and scratches
injections
bites
surgery
Preferred Portal of Entry


Just because a pathogen enters your body it
does not mean it’s going to cause disease.
pathogens - preferred portal of entry
Preferred Portal of Entry

Streptococcus pneumoniae
• if inhaled can cause pneumonia
• if enters the G.I. Tract, no disease

Salmonella typhi
• if enters the G.I. Tract can cause Typhoid Fever
• if on skin, no disease
Number of Invading Microbes


LD50 - Lethal Dose of a microbes toxin that
will kill 50% of experimentally inoculated
test animal
ID50 - infectious dose required to cause
disease in 50% of inoculated test animals
• Example: ID50 for Vibrio cholerea 108 cells
(100,000,000 cells)
• ID50 for Inhalation Anthrax - 5,000 to 10,000
spores ????
How do Bacterial Pathogens
penetrate Host Defenses?
1. Adherence - almost
all pathogens have a
means to attach to host
tissue
Binding Sites
adhesins
ligands
Some cells use fimbriae to
adhere.
Fimbriae can play
a role in tissue
tropism. Example attachment of Candida
to vaginal epithelial
cells
Adhesins and ligands are usually
on Fimbriae

Neisseria gonorrhoeae
 ETEC
(Entertoxigenic E. coli)

Bordetello pertussis
Bacteria typically employ proteins known as Adhesins to
attach to host tissues, which usually are located on ends of
fimbriae.
Alternatively, adhesins can consist of glycocalyx.
2. Capsules







K. pneumoniae
Prevent phagocytosis
attachment
Streptococcus
pneumoniae
Klebsiella pneumoniae
Haemophilus
influenzae
Bacillus anthracis
Streptococcus mutans
Avoidance of Phagocytosis
Capsules are Involved in
avoidance of phagocytemediated recognition
and attachment.
Cell Wall Components
M protein: Found on cell surface and
fimbriae of Streptococcus pyogenes.
Mediates attachment and helps resist
phagocytosis. M-protein is heat and
acid resistant
Waxes [ Mycolic Acid]: In cell wall
of Mycobacterium tuberculosis helps
resist digestion after phagocytosis and
can multiply inside WBC.
3. Enzymes

Many pathogens secrete enzymes that
contribute to their pathogenicity
Enzymes and toxins that harm eukaryotic cells.
A. Leukocidins

Attack certain types of WBC’s

1. Kills WBC’s which prevents phagocytosis
2. Releases & ruptures lysosomes

• lysosomes - contain powerful hydrolytic
enzymes which then cause more tissue damage
B. Hemolysins - cause the lysis of RBC’s
Streptococci
1. Alpha (α) Hemolytic Streptococci
- secrete hemolysins that cause the incomplete
lysis or RBC’s
Incomplete
Lysis of RBC
2. Beta (β) Hemolytic Streptococci
- secrete hemolysins that cause the complete lysis
of RBC’s
Complete
Lysis of RBC
3. Gamma (γ) Hemolytic Streptococci
- do not secrete any hemolysins
C. Coagulase - cause blood to
coagulate


Blood clots protect bacteria from
phagocytosis from WBC’s and other host
defenses
Staphylococcus aureus - are often coagulase
positive
Fibrinogen ----------------- Fibrin ( Clot)
D. Kinases - enzymes that dissolve
blood clots


1. Streptokinase - Streptococci
2. Staphylokinase - Staphylococci

Helps to spread bacteria - Bacteremia

Streptokinase - used to dissolve blood clots in the
Heart (Heart Attacks due to obstructed coronary blood
vessels)
E. Hyaluronidase

Breaks down Hyaluronic acid (found in
connective tissues)



“Spreading Factor”
mixed with a drug to help spread the drug
through a body tissue
Streptococci, Staphylococci, Clostridia and
pneumococci.
F. Collagenase

Breaks down collagen (found in many connective
tissues)

Clostridium perfringens - Gas Gangrene
• uses this to spread through muscle tissue
Tissue Damage Caused by Microbial
Enzymes of Clostridium perfringens
Severe gangrene caused by Clostridium perfringens.
Source: Tropical Medicine and Parasitology, 1997
G. Necrotizing Factor
- causes death (necrosis) to tissue cells
“Flesh Eating Bacteria”
Necrotizing fasciitis
H. Lecithinase



Destroys lecithin ( phosphatidylcholine)
component of plasma membrane.
Allowing pathogen to spread
Clostridium perfringens
Summary of How Bacterial
Pathogens Penetrate Host Defenses



1. Adherence
2. Capsule
3. Enzymes
•
•
•
•
A. leukocidins
B. Hemolysins
C. Coagulase
D. Kinases
E. Hyaluronidase
F. Collagenase
G. Necrotizing Factor H. Lecithinase
4. Toxins



Poisonous substances produced by
microorganisms
toxins - primary factor - pathogenicity
220 known bacterial toxins
• 40% cause disease by damaging the Eukaryotic
cell membrane

Toxemia
• Toxins in the bloodstream
• Toxigenicity: Capacity of microorganisms to
produce toxins.
Two Types of Toxins

1. Exotoxins
• secreted outside the bacterial cell

2. Endotoxins
• part of the outer cell wall of Gram (-) bacteria.
??
Exotoxins versus Endotoxins
I- Exotoxins

Mostly seen in Gram (+) Bacteria

Most gene that code for exotoxins are
located on plasmids or phages
Three Types of Exotoxins

1. Cytotoxins
• kill cells e.g. Diphtheria toxin

2. Neurotoxins
• interfere with normal nerve impulses.e.g.
Botulinum Toxin

3. Enterotoxins
• effect cells lining the G.I. Tract. e.g. Cholera
toxin or choleragen.
Response to Toxins

If exposed to exotoxins: antibodies against the
toxin (antitoxins)
 Exotoxins inactivated ( heat, formalin or phenol)
no longer cause disease, but stimulate the
production of antitoxin
• altered exotoxins - Toxoids
 Toxoids - modified toxin by heat, chemical,
radiation, that have lost their toxicity. Injected to
stimulate the production of antitoxins and provide
immunity.
Example: DPT Vaccine

D - Diphtheria
• Corynebacterium diphtheriae

P - Pertussis
• Bordetello pertussis

T - Tetanus
• Clostridium tetani
DPT - Diphtheria Toxoid
Pertussis Antigen
Tetanus Toxoid
Required Immunizations in Jordan






1. Diphtheria
2. Pertussis
3. Tetanus
4. Measles
5. Mumps
6. Rubella






Corynebacterium diphtheriae
Bordetello pertussis
Clostridium tetani
Measles virus
Mumps virus
Rubella virus
• German Measles

7. Polio
 9. Hepatitis B

Polio virus
 Hepatitis B Virus
Most genes that code for exotoxins - plasmids
or phages

Lysogenic convergence
 Diphtheria
 Cytotoxin inhibits
protein synthesis resulting in cell death
 Pseudomembrane
• fibrin, dead tissue,
bacterial cells
Lysogenic Convergence


Scarlet Fever
Streptococcus pyogenes
• lysogenic convergence

cytotoxin - damages blood capillaries and results in a
skin rash
• Strep Thoat with a rash
Rash of Scarlet Fever Caused by Erythrogenic
Toxins of Streptococcus pyogenes
Diseases Caused by Staphylococcal Toxins
Scalded Skin Syndrome
Toxic Shock Syndrome
Diseases caused by Neurotoxins

Botulism
• Clostridium botulinum
• Gram (+), anaerobic, spore-forming rod, found in
soil
• works at the neuromuscular junction
• prevents impulse from nerve cell to muscle cell
• results in muscle paralysis
Tetanus (Lock Jaw)


Clostridium tetani
Gram (+), spore-forming, anaerobic rod
 neurotoxin acts on nerves, resulting in the
inhibition of muscle relaxation
 tetanospasmin - “spasms” or “Lock Jaw”
Muscle Spasms of Tetanus are Caused by
Neurotoxin of Clostridium tetani
Neonatal Tetanus (Wrinkled brow and risus sardonicus)
Source: Color Guide to Infectious Diseases, 1992
Diseases caused by Enterotoxins

Cholera
• Vibrio cholerae
• Gram (-) comma
shaped rods
Cholera toxin

Converts ATP into cAMP
 causes cells to excrete Cl- ions and inhibits
absorption of Na+ ions
 Electrolyte imbalance
 H2O leaves by osmosis
 H2O Loss (Diarrhea)
 Two polypeptides: A (active) and B (binding).
The A subunit of enterotoxin causes epithelial
cells to discharge large amounts of fluids and
electrolytes.
Severe cases, 12 - 20 liters of liquid lost
in a day

Untreated cases - Mortality Rate about 50%

Mortality may be reduced to about 1%
• administering fluids and electrolytes
Vibrio Enterotoxin Causes Profuse Watery Diarrhea
Rice-water stool of cholera. The A subunit of enterotoxin causes
epithelial cells to discharge large amounts of fluids and electrolytes.
Source: Tropical Medicine and Parasitology, 1995
EHEC (Enterohemorrhagic E. coli)



E. coli (0157:H7)
enterotoxin causes a hemolytic inflammation
of the intestines
results in bloody diarrhea
• Toxin
•
•
•
•
•
alters the 60S ribosomal subunit
inhibits Protein Synthesis
Results in cell death
lining of intestine is “shed”
Bloody Diarrhea (Dysentary)
More on Toxins
II- Endotoxins
• Part of outer membrane surrounding gram-negative
bacteria.
• Endotoxin is lipid portion of lipopolysaccharides (LPS),
called lipid A.
• Effect exerted when gram-negative cells die and cell
walls undergo lysis, liberating endotoxin.
• All produce the same signs and symptoms:
• Chills, fever, weakness, general aches, blood clotting
and tissue death, shock, and even death. Can also
induce miscarriage.
• Fever: Pyrogenic response is caused by endotoxins.
Exotoxins vs. Endotoxins
Endotoxin is LPS
Endotoxins (Continued)
• Endotoxins do not promote the formation of
effective antibodies.
• Organisms that produce endotoxins include:
•
•
•
•
Salmonella typhi
Proteus spp.
Pseudomonas spp.
Neisseria spp.
• Medical equipment that has been sterilized may
still contain endotoxins.
• Limulus amoebocyte assay (LAL) is a test used to
detect tiny amounts of endotoxin.
Events leading to fever:
• Gram-negative bacteria are digested by
phagocytes.
• LPS is released by digestion in vacuoles, causing
macrophages to release interleukin-1 (IL-1).
• IL-1 is carried via blood to hypothalamus, which
controls body temperature.
• IL-1 induces hypothalamus to release
prostaglandins, which reset the body’s
thermostat to higher temperature.
Microbial Mechanisms of Pathogenicity:
How Microorganisms Cause Disease
III. B. The Normal Flora of
Humans

Types of Symbiosis
• Mutualism
• A symbiotic relationship in which both
species benefit
• Commensalism
• A symbiotic relationship in which one
species benefits, and the other species is
neither helped nor harmed
III. B. The Normal Flora of
Humans

Types of Symbiosis (cont.)
• Parasitism
• A symbiotic relationship in which one
species benefits, and the other species is
harmed
• Generally, the species that benefits (the
parasite) is much smaller than the species
that is harmed (the host)
III. B. The Normal Flora of
Humans

Normal flora is present in
• skin
• upper respiratory tract
• oral cavity
• intestine, especially large intestine
• vaginal tract

Very little normal flora in eyes & stomach
III. B. The Normal Flora of
Humans

Notably absent in most all internal organs
• Absent in:
• lower respiratory tract
• muscle tissue
• blood & tissue fluid
• cerebrospinal fluid
• peritoneum
• pericardium
• meninges
III. B. The Normal Flora of
Humans

Benefits of the normal flora
• Nutrient production/processing
eg Vitamin K production by E. coli
• Competition with pathogenic microbes
• Normal development of the immune system

Normal flora and opportunistic infections
III. C. Generalized Stages of
Infection
1. Entry of Pathogen
• Portal of Entry
2. Colonization
• Usually at the site of entry
3. Incubation Period
• Asymptomatic period
• Between the initial contact with the microbe
and the appearance of the first symptoms
III. C. Generalized Stages of
Infection
4. Prodromal Symptoms
• Initial Symptoms
5. Invasive period
• Increasing Severity of Symptoms
• Fever
• Inflammation and Swelling
• Tissue Damage
• Infection May Spread to Other Sites
III. C. Generalized Stages of
Infection
6. Decline of Infection
5. Convalescence
Course of Infectious Disease
Convalescence is
a time of
recuperation and
recovery from
illness.
Incubation period is
the interval between
exposure and
illness onset.
Depending on various
factors an individual may
still be infectious during
either incubation or
convalescence.