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Medical Microbiology. Microbial Pathogenesis and Host-Parasite Relationships. BIOL 533 Lecture 2. Normal Flora. General aspects Remember definition: organisms frequently found on or within body of healthy individuals Most are bacteria, but some are viruses, fungi, and protozoa

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normal flora
Normal Flora
  • General aspects
    • Remember definition: organisms frequently found on or within body of healthy individuals
    • Most are bacteria, but some are viruses, fungi, and protozoa
      • We do not carry all of them all of the time
      • Each person has individualized normal flora
normal flora3
Normal Flora
  • Some are found only on body; others also found in environment
  • Problem: some people have transient normal flora (pathogens)
    • Example: about 10% of population have meningococcus or pneumococcus as normal flora
importance
Importance
  • Opportunistic infections: normal flora in unusual sites; for example:
    • Bacteriodes from intestine into deeper tissues as a result of trauma (or surgery)
    • Staphylococci from skin and nose
    • Streptococci and Gram— cocci from throat and mouth
importance5
Importance
  • Depends on pathogen and on defenses of host:
    • Candida (yeast) causes pneumonia in people undergoing cancer chemotherapy
    • Pneumocystis carinii (common inhabitant of lung) causes pneumonia and death in AIDS patients
immune stimulation
Immune Stimulation
  • Antigenic stimulation by normal flora— do not have high antibody titers
    • Serve as defense mechanism even in low concentration
    • Bacterial stimulation leads to production of IgA that is secreted through mucus membranes
      • Probably interfere with colonization of deeper tissues
immune stimulation7
Immune Stimulation
  • Sometimes antibodies elicited by normal flora cross-react with normal tissue:
    • Antibodies against ABO blood group substances:
      • A - make B antibodies
      • B - make A antibodies
      • O - make antibodies against both
    • Why? Bacteria from intestinal flora contain Ag that cross-react with both A & B blood substances
immune stimulation8
Immune Stimulation
  • Cross-reactivity does not normally cause disease
    • Possible for antibodies cross-reactive to microbial Ag to cause problem
      • Lupus erythematosus—production of Ab against host DNA
        • Some evidence that Ag may be cross-reacting bacterial LPS
      • May cross-react with pathogen (meningococcus)
physical chemical aspects
Physical & Chemical Aspects
  • Keeps out invaders
    • Mechanisms:
      • Physical advantage of previous occupancy
      • Some produce bacteriocins or antibiotics
    • Relevance to lab work: E. coli K-12 cannot compete with intestinal flora
physical chemical aspects10
Physical & Chemical Aspects
  • Antibiotic effects: wipes out normal flora
    • Both endogenous and exogenous organisms can cause disease
      • Infecting dose of Salmonella decreases one million-fold when mice given streptomycin
      • Patients treated with some potent antibiotics:
        • Suffer from diarrhea due to overgrowth of yeasts, and staphylococci
        • Administration of clindmycin-Clostridium difficile (minor member of normal flora) causes pseudomembranous colitis
physical chemical aspects11
Physical & Chemical Aspects
  • Role in human nutrition and metabolism
    • E. coli and Bacteriodes synthesize vitamin K
    • Metabolism of key compounds involves excretion from liver into intestine and their return to the liver
physical chemical aspects12
Physical & Chemical Aspects
  • Important for sex hormones and bile salts
    • Excreted through bile in conjugated form as glucuronides or sulfate, but cannot be reabsorbed in this form
    • Members of intestinal bacterial flora make glucuronidases and sulfatases that can deconjugate these compounds
      • Physiological role not known
physical chemical aspects13
Physical & Chemical Aspects
  • Source of carcinogens
    • Large intestinal flora
      • Many potential carcinogens are only active after being modified
        • Some modifications are carried out by enzymes of intestinal bacteria; example: cyclamate converted to bladder carcinogen (cyclohexamine) by bacterial sulfatases
      • Importance of carcinogen production not clear
ecology of normal flora
Ecology of Normal Flora
  • Use of germ-free animals
    • Immune systems not well developed
    • Have to be fed vitamins
ecology of normal flora15
Ecology of Normal Flora
  • Parts of body colonized
    • Contain large numbers:
      • Skin
      • Respiratory tract (nose and oropharynx)
      • Digestive tract (mouth and large intestine)
      • Urinary tract (anterior parts of urethra)
      • Genital system (vagina)
      • Most are strict anaerobes
ecology of normal flora16
Ecology of Normal Flora
  • Parts of body colonized
    • Contain small numbers, many in transit:
      • Rest of respiratory and digestive tracts
      • Bladder
      • Uterus
    • Finding pathogens at these sites is suggestive of disease, but not proof
ecology of normal flora17
Ecology of Normal Flora
  • Sterile sites—pathogens in these definitely indicate disease
    • Blood
    • Cerebrospinal fluid
    • Synovial fluid
    • Deep tissues
identification of pathogens
Identification of Pathogens
  • Traditional: associate disease with organism
koch s postulates
Koch’s Postulates
  • Bacterium found in all patients having disease and it or its products found in all body parts affected
  • The bacterium should be isolated and grown in pure culture
koch s postulates21
Koch’s Postulates
  • Pure culture inoculated into susceptible animal should produce disease
  • Same bacterium re-isolated in pure culture from experimental animal
koch s postulates22
Koch’s Postulates
  • Some assumptions questioned in light of more modern approaches and new information about host-parasite interaction
challenge to postulate 1
Challenge to Postulate #1
  • Implies virulence resides only with pathogen and not at all with host
  • Clearly, susceptibility of host is as important
    • Immuno-compromised individuals vs. healthy adults prove the point
    • Minor pathogen causes disease in immuno-compromised individuals only
challenge to postulate 2
Challenge to Postulate #2
  • Places considerable emphasis on culturing organisms in pure culture
  • Some organisms have not been cultured in laboratory media
challenge to postulate 225
Challenge to Postulate #2
  • For example, Treponema pallidium, Mycobacterium leprae clearly cause disease:
    • Antibiotics cause both symptoms and organisms from tissues to disappear
    • Immune response in infected patients to surface Ag of bacteria from infected tissue
challenge to postulate 3
Challenge to Postulate #3
  • Implies all members of a bacterial species are equally virulent and only a single species causes disease
    • Different strains of species vary in virulence
    • Different strains can cause different diseases
    • Same symptoms caused by numerous organisms
    • Disease caused by multiple organisms
challenge to postulate 327
Challenge to Postulate #3
  • Well known fact that cultivation of some pathogens can lead to loss of virulence factors
challenge to postulate 4
Challenge to Postulate #4
  • Requires pathogen be reinoculated into an animal and produces symptoms of disease
    • Some diseases don’t affect animals, or cause different symptoms from human form
  • Therefore, to be practical, Koch’s Postulates require animal models
molecular version
Molecular Version
  • Emphasis shifted from identification of pathogens to identification of virulence factors
  • Not complete agreement on requirements to prove a particular gene or product plays a role in disease, but criteria widely accepted
molecular version31
Molecular Version
  • Gene or product found in strains that cause disease and not in avirulent bacteria
    • If gene found in organisms not known to cause disease, gene should be mutated to less active or inactive form, or not expressed
molecular version32
Molecular Version
  • Disrupting gene in virulent strain reduces or eliminates its virulence
    • Introduction of cloned gene into avirulent strain should make it virulent
    • Systems with multiple genes:
      • These other genes would also have to be modified or introduced
molecular version33
Molecular Version
  • Gene is expressed in bacteria inside host sometime during disease process
  • Ab to gene product should be protective or in cases where cell-mediated immunity involved, gene product should elicit protective immunity
identification without culturing
Identification without Culturing
  • Combine PCR: Polymerase Chain Reaction with 16S r-RNA phylogeny
  • 16S r-RNA found in all bacteria
  • Conserved (domain) and variable (particular organism) sequences
identification without culturing35
Identification without Culturing
  • Sizable database and similarities in sequence correspond well to evolutionary relationships
  • Sequence will either identify it as member of known or unknown species
identification without culturing36
Identification without Culturing
  • PCR primers that recognize two conserved regions of 16S rRNA flanking a variable region are used to amplify and clone a DNA segment from a clinical speciman
    • If amplified segment is obtained, indicates bacteria present in speciman
    • It can be sequenced to identify bacterium
identification without culturing37
Identification without Culturing
  • Fluorescently labeled probe of sequence can then visualize bacterium in clinical speciman
  • Rules out PCR amplification of contaminating DNA from other sources
lecture two
Lecture Two
  • Questions?
  • Comments?
  • Assignments...