Bacterial Pathogenicity

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Bacterial Pathogenicity Infections
Stijn van der Veen
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Pathogenicity Infection

• Pathogenicity is the ability of a microbe to gain
  entry to the hosts tissue and bring about a
  physiological or anatomical change, resulting in
  altered health and leading to disease.
• Infection refers to the multiplication of a
  microbe in a host and the competition for
  supremacy taking place between them.
• A host whose resistance is strong remains
  healthy, but if the host loses the competition,
  disease develops.

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Disease

• Disease refers to any change from the general
  state of good health.
• Infectious disease is a disease
• condition caused by the presence
• or growth of infectious microbes.
• Disease and infection are
• NOT synonymous a host
• may be infected without
• suffering disease.

Infectious disease deaths worldwide in 2008
total 15 million.
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Disease Communicable vs. Noncommunicable

• 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.
• Epidemiology
• The study of patterns, causes and transmission of
  disease.

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Disease in the population

• 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.

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Infections acute vs. chronic

• 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.

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Infections primary vs. secondary

• 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.

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Infections localized vs. systemic

• 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.

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Infections clinical vs. subclinical

• Clinical infection
• An infection with obvious observable or
  detectable symptoms.
• Subclinical infection
• An infection with few or no obvious symptoms.

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Infections exogenous vs. endogenous

• Exogenous infection
• An infection established by a pathogen from the
  environment.
• Endogenous infection
• An infection caused by a microbial member of the
  normal microbiota of the host.
• Opportunistic infection
• An infection caused commensals taking advantage
  of a shift in the delicate balance to one
  favoring the microbe.

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Indigenous human microbiota

• Indigenous microbiota consist of microbes that
  established a permanent relationship with various
  parts of the body. This is called symbiosis.
• Transient microbiota is more temporary and found
  for a limited period.
• If symbiosis is beneficial for both organisms,
  the relationship is
• called mutualism.
• If symbiosis is only beneficial for
• the microbe, the relationship is
• called commensalism.

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Indigenous microbiota

• Nutrient production / processing, e.g. vitamin K
  production by E. coli.
• Competition with pathogenic microbes.
• Normal development of the immune system.
• Indigenous microbiota is absent in
• Lower respiratory tract
• Muscle tissue
• Blood tissue fluid
• Cerebrospinal fluid
• Peritoneum
• Pericardium
• Meninges

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Virulence

• The likelihood that a disease results from an
  infection is determined by
• The virulence of the microbe
• The number of microbes in the infection
• The resistance of the host
• Virulence is the degree of pathogenicity of a
  microbe.
• This term is often used to describe or compare
  strains within a species.

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Lethal dose (LD) infectious dose (ID)

• The virulence of a microbe (or the toxicity of a
  toxin it produces) is often expressed as the LD50
  or ID50.
• LD50 is the number of microbes needed to kill 50
  of the inoculated hosts (a test population) under
  standard conditions.
• The ID50 is the number of microbes needed to
  cause disease in 50 of the test population under
  standard conditions.
• The lower the LD50 and ID50 of a microbe, the
  more virulent the microbe is.

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Predisposing disease factors

• Certain predisposing factors may make the body
  more susceptible to disease or may alter the
  course of a disease.
• Gender
• Nutritional status
• Weather and climate
• Fatigue
• Age
• Habits
• Life style
• Pre-existing illness
• Emotional disturbance
• Chemotherapy

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Stages of Infection

• Transmission of the pathogen
• Entry of the pathogen
• Portal of entry
• Colonization (usually at the site of entry)
• Incubation period
• Asymptomatic period between entry of pathogen and
  appearance of first symptoms
• Prodromal (initial) symptoms
• Invasive period
• Increasing severity of symptoms, fever,
  inflammation and swelling, tissue damage,
  spreading of infection.
• Decline of infection
• Convalescence

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Transmission

• The route of transmission is dependent on the
  reservoir of the infection, which is the source
  of the infectious agent.
• Direct transmission
• Transmission from person to person, for instance
  by a carrier
• Direct transmission can be through contact of the
  skin or by aerosols (airborne).
• Indirect transmission
• Transmission through an intermediate source
• Indirect transmission can be through food, water,
  fomites or animal vectors.

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Carriers, fomites animal vectors

• Carriers are individuals who carries an
  infectious agent without manifesting symptoms,
  yet who can transmit the agent to another
  individual.
• Fomite are inanimate objects capable of being an
  intermediate in the indirect transmission of an
  infectious agent.
• Animal vectors are animals that can transmit an
  infectious agent to humans.
• Mechanical animal vectors physically transmit the
  infectious agent, 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 transmit the infectious
  agent and the agent must incubate or grow in the
  animal as part of the agents developmental
  cycle, e.g. the transmission of malaria by
  infected mosquitos.

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Portal of entry

• The portal of entry is the avenue by which
  pathogens gain entrance to the host
• Mucous membranes
• Respiratory tract
• Gastrointestinal tract
• Urogenital system
• Conjunctiva of the eye
• Skin
• Parenteral route

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Colonization

• After gaining entrance, pathogens need to
  colonize the host tissues, which is usually at
  the site of entry.
• The initial step in colonization of host tissues
  is attachment.
• Attachment can be specific or non-specific
• Specific attachment is dependent
• on the interaction between an
• adhesin (ligand) and its receptor.
• Non-specific attachment is
• mediated by Van der Waals and
• electrostatic forces and hydrogen
• bonding.

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Incubation period

• After pathogens gain access to the host and are
  able to establish attachment to host tissue, the
  incubation period starts.
• The incubation period is the time between entry
  of the host and the appearance of primary
  symptoms.
• The length of the incubation period varies
  greatly and is dependent on several factors
• Number of invading organisms
• Generation time
• Virulence
• Level of host resistance
• Location of entry

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Prodromal phase

• The prodromal phase is the period of first onset
  of symptoms
• For many diseases it is characterized by
  indistinct general symptoms like
• Nausea
• Headache
• Muscle ache
• For some diseases the initial symptoms are
  clearly recognizable.

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Invasive phase

• The invasive or acute phase is the stage when
  signs and symptoms are of greatest intensity.
• Increasing severity of symptoms
• Fever,
• Inflammation and swelling
• Tissue damage
• Spreading of infection
• The length of this phase is quite variable and is
  dependent on
• Bodys response to the pathogen
• Virulence of the pathogen

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Decline of infection convalescence

• When symptoms start to subdue, the period of
  decline starts.
• Sweating is common to release excess heat and
  waste products.
• When the host start to recover, the period of
  convalescence start.
• During this period, the bodys systems return to
  normal.

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Overview of bacterial infections
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Bacterial pathogenicity
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Portal of entry respiratory tract

• Respiratory Tract
• Microbes inhaled into mouth or nose in droplets
  of moisture or dust particles
• Easiest and most
• frequently used
• portal of entry.

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Respiratory diseases

• Pneumonia
• Streptococcus pneumonia, Haemophilus influenzae,
  Staphylococcus aureus, Mycoplasma pneumoniae,
  Legionella pneumophila
• Tuberculosis
• Mycobacterium tuberculosis
• Diphtheria
• Corynebacterium diphtheriae
• Whooping cough
• Bordetella pertussis

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Portal of entry gastrointestinal tract

• Pathogens gain entrance of the gastrointestinal
  (G.I.) tract through contaminated food or water,
  or dirty hands.
• Most microbes that enter the G.I.
• tract are generally eliminated
• by the gastric acid, bile, and
• antibacterial enzymes in the
• small intestine.

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GI tract diseases

• Campylobacteriosis
• Campylobacter sp.
• Salmonellosis
• Salmonella sp.
• Escherichia coli infections
• EHEC, ETEC, EIEC, EPEC
• Gastritis / peptic ulcers
• Helicobacter pylori
• Shigellosis
• Shigella sp.
• Cholera
• Vibrio cholerae
• Clostridium sp. / Staphylococcus aureus

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Fecal - Oral diseases

• Pathogens enter the G.I. tract at one end and
  exit at the other end.
• Spread by contaminated hands, food, and water.
• Poor personal hygiene.

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Portal of entry urogenital system

• Sexually transmitted diseases/infections
  (STD/STI)
• Diseases that are spread by sex, including
  vaginal intercourse and oral or anal sex. The
  risk of spreading of the disease is great due to
  the lack of primary symptoms (particularly in
  women).
• Urinary tract infections (UTI)
• Infection of the lower urinary tract is known as
  cystitis or bladder infection.
• Infection of the upper urinary tract is called
  pyelonephritis or kidney infection.

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Urogenital tract diseases

• Sexually transmitted diseases
• Gonorrhea
• Neisseria gonorrhoeae
• Syphilis
• Treponema pallidum
• Chlamydia
• Chlamydia trachomatis
• Urinary tract infections
• Escherichia coli
• Staphylococcus saprophyticus

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Portal of entry conjunctiva

• Conjunctiva are the mucus membranes that cover
  the eyeball and lines of the eyelid.
• The conjunctiva are generally sterile places.
• Conjunctiva infections include
• Staphylococcus aureus
• Neisseria gonorrhoeae
• Chlamydia trachomatis

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Portal of entry skin

• The skin is the largest organ of the body.
• When unbroken the skin is an effective barrier
  for most microbes.
• Some microbes can gain entrance through openings
  in the skin, e.g. hair follicles and sweat glands.

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Portal of entry parenteral

• Microbes are directly deposited into the tissues
  below the skin or mucus membranes.
• Punctures and scratches
• Injections
• Bites
• Surgery
• Examples include
• Tetanus (Clostridium tetani) from rusty nails
• Lyme disease (Borrelia burgdorferi) from tick
  bites
• Staphylococcus infections from surgery
• Etc.

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Preferred portal of entry

• Just because a pathogen enters your body it does
  not mean its going to cause disease.
• Pathogens have a preferred portal of entry.
• For instance
• Streptococcus pneumoniae
• When inhaled can cause pneumonia
• When it enters the G.I. tract, no disease
• Salmonella typhi
• When it enters the G.I. tract it can cause
  typhoid fever.
• When it is on the skin, no disease

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Bacterial mechanisms of pathogenicity
Virulence factors
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Virulence factors
Damage to host tissues
Production and delivery of various factors
Attachment to host tissues
Replication and evasion of immunity
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Adherence

• Many pathogens adhere to host cells at their
  preferred portal of entry because they contain
  specific adhesins.
• Adhesins are proteins or sometime cabohydrates
  that are located on the bacterial cell surface
  and are able to interact directly with structures
  on the host cell surface, thereby mediating
  attachment.
• Adhesins are often associated with bacterial
  pili, flagella, or capsules.

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Adhesins

• Neisseria gonorrhoeae, Neisseria meningitidis,
  Bordetella pertussis, Salmonella sp., ETEC, and
  many other bacterial pathogens have ligands on
  the tip of pili that are able to directly adhere
  to structures on the surface of epithelial cells.
• Streptococcus mutans adheres to the surfaces of
  tooth enamel via an extracellular polysaccharide
  that it secretes.
• Streptococcus pyogenes binds to fibronectin on
  the surface of epithelial cells via a cell wall
  protein called M-protein and via lipoteichoic
  acids in the cell wall.
• Etc.

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Capsule

• Capsule contributes to virulence of pathogens
• Mediates adherence
• Protects against phagocytosis
• Protects against antimicrobial compounds secreted
  by host cells, such as antimicrobial peptides and
  ROS.
• Examples include
• Neisseria meningitidis
• Streptococcus pneumoniae
• Klebsiella pneumoniae
• Haemophilus influenzae
• Bacillus anthracis
• Streptococcus mutans

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Type III secretion system

• syringe-like multi-protein structure able to
  penetrate host cells and deliver effectors
  (mostly small proteins or toxins) directly into
  the host cytosol.
• The effectors modulate host functions or
  stimulate uptake into non-phagocytic cells.
• Similar in structure to type II secretion systems
  and type IV pili.
• Found in some gram negative bacteria.

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Actin polymerization

• Some bacteria recruit actin to provide the force
  for intracellular movement.
• Means to escape autophagy, which is an
  intracellular antimicrobial resistance mechanism.
• Means to move between cells.
• Examples
• Listeria monocytogenes
• Shigella sp.

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Bacterial cloaking

• S. aureus produces protein A and S. pyogenes
  produces Protein G which bind the Fc portion of
  IgG
• Binding of IgG to the bacterial cell surface
  provides protection against phagocytosis.

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Leukocidins

• Leukocidins are enzymes that destroy circulating
  white blood cells (WBC) such as neutrophils and
  macrophages, which are immune cells designed to
  phagocytize and destroy pathogens.
• Leukocidins destroy the cell membrane of WBC and
  trigger the release and rupture of lysosomes.
• Lysosomes contain powerful hydrolytic enzymes
  which then cause more tissue damage.
• Example
• Staphylococcus aureus
• Streptococcus pyogenes
• Streptococcus pneumoniae

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Coagulase

• Coagulase catalyses the formation of blood clots
  from Fibrinogen proteins in the human blood.
• Blood clots protect bacteria from phagocytosis by
  WBCs and other host defenses.
• Example
• Staphylococcus aureus

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Kinase

• Kinases have the ability to dissolve blood clots
  used as a defense by the body to restrict and
  isolate an infected area.
• Kinases help bacteria to spread and cause
  bacteremia
• Examples
• Streptokinase - Streptococcus sp
• Staphylokinase - Staphylococcus aureus

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Hyaluronidase

• Hyaluronidase breaks down hyaluronic acid, which
  is a polysaccharide that connects cells in
  tissues.
• It is called the spreading factor because it
  enhances penetration of bacteria into tissues.
• Examples
• Streptococcus sp.
• Staphylococcus aureus
• Clostridia sp.

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Hemolysins

• Hemolysins combine with the membranes of red
  blood cells, causing it to lyse.
• Lysing of red blood cells provide pathogens with
  the iron from hemoglobin, which is required for
  many metabolic processes.
• a, ß, and ? hemolyses
• Example
• Streptococcus sp
• Staphylococcus aureus

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Collagenase

• Collagenase breaks down collagen, which is found
  in many connective tissues.
• Collagenase allows pathogens to spread through
  muscle tissue.
• Example
• Clostridium perfringens - Gas Gangrene

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Overview of enzymatic virulence factors
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Toxins

• Toxins are poisonous substances produced by some
  microbes that is important for pathogenicity.
• There are 220 known bacterial toxins and 40
  cause disease by damaging the eukaryotic cell
  membrane.
• The capacity to produce toxins is called
  toxigenicity.
• Toxemia refers to symptoms caused by toxins in
  the blood.
• There are two basic types
• of toxins
• Exotoxins
• Endotoxins

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Exotoxins

• Most exotoxins are produced by gram positive
  bacteria.
• Exotoxins are soluble in body fluids and are
  transported rapidly throughout the body.
• Exotoxins are frequently encoded from genes that
  are carried on plasmids or in lysogenic
  bacteriophages.
• Exotoxins are among the most lethal toxins known
  to man. For example, 1 mg of the botulinum toxin
  can kill 1 million guinea pigs.

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Toxoids

• Exotoxins are disease specific and are frequently
  the main cause of the disease.
• The host can produce anti-toxins (antibodies)
  which can provide immunity against the effects of
  the toxin.
• Exotoxins can be inactivated by heat,
  formaldehyde, iodine or other substances to
  produce toxoids.
• Toxoids can be used for vaccination to produce
  anti-toxin antibodies.

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Exotoxin structure

• Many have an A (toxic effect)/B (binding)
  structure

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Botulinum toxin

• Botulinum toxin produced by Clostridium
  botulinum.
• This toxin is unique in that it is not released
  until the death of the microorganism.
• It acts at the neuromuscular junction to prevent
  the transmission of nerve impulses leading to
  flaccid paralysis and death from respiratory
  failure.

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Tetnus toxin

• Tetanus toxin produced by Clostridium tetani.
• This toxin causes excitation of the CNS leading
  to spasmodic contractions and death from
  respiratory failure.
• The disease it produces is also called
  lockjaw.

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Diphtheria toxin

• Diphtheria toxin produced by Corynebacterium
  diphtheriae.
• This toxin inhibits protein synthesis in
  eukaryotic cells and can cause death.

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Vibrio enterotoxin

• Vibrio enterotoxin produced by Vibrio cholera.
  
• This toxin alters the water and electrolyte
  balance in the intestine leading to a very
  severe, life threatening, watery diarrhea.

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Endotoxins

• Endotoxins are part of the outer membrane of most
  gram negative bacteria.
• Endotoxins are the lipid A part of the LPS.
• Exert their effects when gram negative bacteria
  die and the LPS is released.
• All produce the same signs and symptoms, i.e.,
  they are not disease specific.
• These symptoms include fever (pyrogenic
  response), weakness, generalized aches and pains
  and sometimes shock.
• Antibodies produced against them do not protect
  the host from their effects.
• Only large doses are lethal.

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Pyrogenic response against endotoxins
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Endotoxin versus exotoxin
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Next lecture

• Antibacterial Agents Conditions