Normal Flora and Bacterial Pathogenesis

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Normal Flora and Bacterial Pathogenesis

• Pin Ling (? ?), Ph.D.
• Department of Microbiology Immunology, NCKU
• ext 5632
• lingpin_at_mail.ncku.edu.tw
• References
• 1. Murray, P. et al., Medical Microbiology (5th
  edition)
• 2. Samuel Baron, Medical Microbiology (4th
  edition)

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Outline

• Normal Flora
• (Commensal Microbes)
• Introduction
• Significance of the Normal Flora
• Distribution of the Normal Flora

• Bacterial Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenic Mechanisms
• Virulence Factors

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Normal Flora and Pathogenesis
Outcomes of exposure to a microorganism
Transient colonization Permanent
colonization Disease
Colonization vs. infection Colonization
establishment of a site of reproduction of
microbes on a person without necessarily
resulting in tissue invasion or
damage. Infection growth and multiplication of a
microbe in or on the body of the host with or
without the production of disease.
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Introduction of Normal Flora

• A diverse microbial flora gt Human body
• Area the skin and mucous membranes
• Time shortly after birth until death
• Number 1014 bacteria gt1013 host cells
• 2. Normal flora may
• a. Aid the host
• b. Harm the host (in sometimes)
• c. Exist as commensals (no effect to the host)
• Viruses and parasites gt NOT normal microbial
  flora
• Most investigators consider that they are not
  commensals and do not aid the host.

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Significance of Normal Flora-I

• The effect of the normal flora on the host was
  not well understood until germ-free animals
  became available.
• Cesarean Section gt Germ-free animals gt
  Isolators w/o detectable pathogens (viruses,
  bacteria others)
• Two interesting observations
• a. the germ-free animals lived almost twice as
  long as their conventionally maintained
  counterparts.
• b. the major causes of death were different in
  the two
• groups.

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Germ-free Animals vs Counterparts
Germ-free Animals Regular Counterparts
Lifespan Twice One
Cause of death Intestinal Atonia Infection
Anatomic Physiological Changes 1. Alimentary lamina propria under-developed 2. No Ab 3. Intestinal epithelial cell renewal rate down half
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Significance of Normal Flora-II

• Normal flora may aid the host in several ways
• Aid in digestion of food
• Help the development of mucosa immunity
• Protect the host from colonization with
  pathogenic microbes.

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Normal Flora competing w/ Invading Pathogens
Adopted from Samuel Baron Medical Microbiology
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Normal flora may act as opportunistic pathogens
Especially in hosts rendered susceptible by 1.
Immuno-suppression (AIDS SCID) 2. Radiation
therapy Chemotherapy 3. Perforated mucous
membranes 4. Rheumatic heart diseaseetc.
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Sites of human body that the normal flora
microbes colonize
Respiratory tract and head outer ear, eye,
mouth, oropharynx, nasopharynx Sterile sites
sinuses, middle ear, brain, lower respiratory
tract (trachea, bronchiole, lung) Gastrointestinal
tract esophagus, stomach, small intestine,
large intestine Genitourinary system anterior
urethra, vagina Sterile sites bladder,
cervix, uterus Skin
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Distribution of Normal Flora in Human Body
Adopted from Smaul Baron Medical Microbiology
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Factors Influencing Normal Flora

1. Local Environment (pH, temperature, redox
   potential, O2, H2O, and nutrient levels).
2. Diet
3. Age
4. Health condition (immune activity)
5. Antibiotics,..etc

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Outline

• Normal Flora
• (Commensal Microbes)
• Introduction
• Significance of the Normal Flora
• Distribution of the Normal Flora

• Bacterial Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenic Mechanisms
• Virulence Factors

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Introduction of Bacterial Pathogenesis

• Infection growth and multiplication of a microbe
  in or on the body of the host with or without the
  production of disease.
• The capacity of a bacterium to cause disease
  reflects its relative pathogenicity.
• 3. Virulence is the measure of the pathogenicity
  of an organism.
• 4. Pathogenesis refers both to the mechanism of
  infection and to the mechanism by which disease
  develops.

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Host Susceptibility

• Susceptibility to bacterial infections
• gt Host Defenses vs Bacterial Virulence
• Host Defenses
• - Barriers (skin mucus) first line
• - Innate Immune Responses (complement,
  macrophages
• cytokines) the early stage
• - Adaptive Immune Responses (Ag-specific B T
  cells) the
• later stage
• Host defenses can be comprised by destructing
  barriers or defective immune response.
• e.x. Cystic Fibrosis gt poor ciliary function gt
  NOT clear mucus efficiently from the respiratory
  tract gt Pseudomonas aeruginosa gt serious
  respiratory distress.

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Strict pathogens are more virulent
and can cause diseases in a normal
person. Opportunistic pathogens are typically
members of normal flora and cause diseases when
they are introduced into unprotected sites,
usually occur in people with underlying
conditions.
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Pathological Mechanisms of Bacterial Infections

• Bacteria-mediated Pathogenesis
• Host-mediated Pathogenesis
• Bacterial virulence factors
• gt bacterial factors causing diseases

Adopted from Samuel Baron Medical Microbiology
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Characteristics of Pathogenic Bacteria

• Transmissibility
• Adherence to host cells
• 3. Invasion of host cells and tissue
• Evasion of the host immune system
• Toxigenicity

• A bacterium may cause diseases by
• Destroying tissue (invasiveness)
• Producing toxins (toxigenicity)
• Stimulating overwhelming host immune responses

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Bacterial Virulence Mechanisms
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Bacterial virulence factors

• Adhesins
• Pili (fimbriae)
• Nonfimbrial adhesins
• Invasion of host cells
• Tissue damage
• Growth byproducts
• Tissue-degrading enzymes
• Immunopathogenesis
• Toxins
• Exotoxins (cytolytic enzymes and A-B
  toxins) enterotoxins
• superantigens
• endotoxin and other cell wall components

Antiphagocytic factors Intracellular
survival Antigenic heterogeneity Antigenic
variation Phase variation Iron
acquisition Siderophores Receptors
for iron-containing molecules Resistance
to antibiotics
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Mechanisms of acquiring bacterial virulence genes
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Entry into the human body
The most frequent portals of entry are the sites
where mucous membranes meet with the skin.
Abnormal areas of mucous membranes and skin are
also frequent sites of entry. Routes Ingestion,
inhalation, trauma, needles, catheters, arthropod
bite, sexual transmission
infection
shedding
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Microbial defenses against host immunologic
clearance Encapsulation (Inhibition of
phagocytosis and serum bactericidal
effect) Antigenic mimicry Antigenic
masking Antigenic or phase variation Intracellul
ar multiplication Escape phagosome Inhibition
of phagolysosome fusion Resistance to lysosomal
enzymes Production of anti-immunoglobulin
protease Inhibition of chemotaxis Destruction
of phagocytes
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Mechanisms for escaping phagocytic clearance and
intracellular survival
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Mechanisms for escaping phagocytic clearance and
intracellular survival
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Mechanisms for escaping phagocytic clearance and
intracellular survival
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Endotoxin-mediated toxicity Fever, leukopenia
followed by leukocytosis, activation of
complement, thrombocytopenia, disseminated
intravasacular coagulation, decreased peripheral
circulation and perfusion to major organs
(multiple organ system failure), Shock and death.
Peptidoglycan, teichoic and lipoteichoic acids of
gram-positive bacteria stimulate pyrogenic acute
phase responses and produce endotoxin-like
toxicity
Back
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Lipid A of lipopolysaccharide is responsible for
endotoxin activity
Pathogenesis of sepsis (septicemia)
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Adopted from Samuel Baron Medical Microbiology
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Regulation of bacterial virulence factors
Environmental factors often control the
expression of the virulence genes. Common
factors temperature, iron availability,
osmolarity, growth phase, pH, specific ions,
specific nutrient factors, bacterial
cell-density, interaction with host cells.
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The severity of a disease is determined by the
inoculum size of the pathogen and the host
conditions, such as congenital defect,
immunodeficiency states and other disease-related
conditions.
The symptoms of a disease are determined by the
function of the tissue affected.
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Transmission of infection
By producing asymptomatic infection or mild
disease, rather than death of the host,
microorganisms that normally live in people
enhance the possibility of transmission from one
person to another.

• Carrier a person or animal with asymptomatic
  infection that can be transmitted to another
  person or animal.
• The clinical symptoms of diseases produced by
  microbes often promote transmission of the
  agents.
• Zoonosis infectious diseases transmitted between
  animals and men.
• Hospital- (nosocomial) vs. community-acquired
  infections

Many bacteria are transmitted on hands
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Adhesion
Back
Adherence of bacterium to epithelial or
endothelial cells allow them to colonize the
tissue. Common adhesins pili (fimbriae), slime,
lipoteichoic acid, surface proteins or
lectins. Biofilm, formed on a surface by the
bacteria that are bound together within a sticky
web of polysaccharide, is a special bacterial
adaptation that facilitates colonization on the
surgical appliances (e.g., artificial valves or
indwelling catheters) and dental plaque. It can
protect the bacteria from host defenses and
antibiotics.
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The bacteria may invade via the M cells
Back
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The A-B toxins
A chain has the inhibitory activity against some
vital function B chain binds to a receptor and
promotes entry of the A chain
Back
Mode of action Inhibition of protein
synthesis Hypersecretion Inhibition of
neurotransmitter release
In many cases the toxin gene is encoded on a
plasmid or a lysogenic phage
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SUMMARY

• 1. Normal flora may aid the host in several ways
• Aid in digestion of food
• Help the development of mucosa immunity
• Protect the host from colonization with
  pathogenic microbes
• 2. Normal flora may act as opportunistic
  pathogens.
• 3. Susceptibility to bacterial infections depends
  on the balance between host defenses and
  bacterial virulence.
• 4. Pathogenic mechanisms of bacterial infections
  include
• Bacteria-mediated Pathogenesis
• Host-mediated Pathogenesis

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Back
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Clonality of bacterial pathogens
Transfer of mobile genetic elements within or
between species can result in transfer of
virulence factors (e.g., pathogenicity
islands). Recombination may occur between
extrachromosomal DNA and the chromosome to
generate new bacterial clone. Different clonal
types of a certain species may cause different
diseases.
Various virotypes of E. coli
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