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Microbial Pathogenesis and HostParasite Relationships

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Most are bacteria, but some are viruses, fungi, and protozoa ... Sizable database and similarities in sequence correspond well to evolutionary relationships ... – PowerPoint PPT presentation

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Title: Microbial Pathogenesis and HostParasite Relationships


1
Microbial Pathogenesis and Host-Parasite
Relationships
Medical Microbiology
  • BIOL 533
  • Lecture 2

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
  • We do not carry all of them all of the time
  • Each person has individualized normal flora

3
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

4
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

5
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

6
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

7
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

8
Immune Stimulation
  • Cross-reactivity does not normally cause disease
  • Possible for antibodies cross-reactive to
    microbial Ag to cause problem
  • Lupus erythematosusproduction of Ab against host
    DNA
  • Some evidence that Ag may be cross-reacting
    bacterial LPS
  • May cross-react with pathogen (meningococcus)

9
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

10
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

11
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

12
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

13
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

14
Ecology of Normal Flora
  • Use of germ-free animals
  • Immune systems not well developed
  • Have to be fed vitamins

15
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

16
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

17
Ecology of Normal Flora
  • Sterile sitespathogens in these definitely
    indicate disease
  • Blood
  • Cerebrospinal fluid
  • Synovial fluid
  • Deep tissues

18
Strategies for Studying Microbial Pathogenesis
Medical Microbiology
  • BIOL 533
  • Lecture 2

19
Identification of Pathogens
  • Traditional associate disease with organism

20
Kochs 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

21
Kochs Postulates
  • Pure culture inoculated into susceptible animal
    should produce disease
  • Same bacterium re-isolated in pure culture from
    experimental animal

22
Kochs Postulates
  • Some assumptions questioned in light of more
    modern approaches and new information about
    host-parasite interaction

23
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

24
Challenge to Postulate 2
  • Places considerable emphasis on culturing
    organisms in pure culture
  • Some organisms have not been cultured in
    laboratory media

25
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

26
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

27
Challenge to Postulate 3
  • Well known fact that cultivation of some
    pathogens can lead to loss of virulence factors

28
Challenge to Postulate 4
  • Requires pathogen be reinoculated into an animal
    and produces symptoms of disease
  • Some diseases dont affect animals, or cause
    different symptoms from human form
  • Therefore, to be practical, Kochs Postulates
    require animal models

29
Identification of Pathogens
  • Molecular version

30
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

31
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

32
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

33
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

34
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

35
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

36
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

37
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

38
Lecture Two
  • Questions?
  • Comments?
  • Assignments...
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