REVIEW FROM LAST LECTURE: Obligate steps for infectious microbes

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REVIEW FROM LAST LECTUREObligate steps for
infectious microbes

• Exposure
• Site of Entry/Interaction
• Attachment/Adherence
• Local evasion (innate)
• Multiplication (colonization/infection)
• Invasion (and potential spread) not all
• Immune Evasion (adaptive)
• Shedding from body to next host (transmission)
• MAIN goal of microbes

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Microbial strategies to evade the host immune
response

• Denise Kirschner, PhD
• Dept of Micro/Immuno
• MICRO 532, Nov 14, 2001
• Chapters 9 and 11 recommended
• Web site for ppt files
• http//malthus.micro.med.umich.edu/532.html

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Introduction

• Goal Multiply and spread to next host
• Evade and invade
• Indigenous microflora (IM) as representative of
  the first steps in colonization.
• List of microbial strategies
• If successful enough, can lead to persistent or
  latent infection i.e. host is not able to clear
• Host all parasites associate with a host

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Indigenous Microflora

• Symbiosis commensals (,0), mutualism (,)
  parasitism (,-).
• Bacteria (and virus) that are symbiotic with us
  that have colonized specific sites in all persons
• Study of IM likened to ecology- science of
  interactions of organisms in their environment
  and with each other.
• Colonize bacteria populations of constant size
  at a given site on/in the body implying
  multiplication rate equals removal/loss rate.
• IM out-number host cells by a factor of 10!

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E. coli
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Establishment of Microflora

• Human fetus is sterile
• Exposed to IM during birth, breast feeding,
  contact with nurses, parents etc.
• Essential for development
• Germ free mice have poorly developed
  reticuloendothelial system and no cross-reactive
  Abs
• Add IM back, development of normal gut functions
• Colonization occurs by 2 days after birth
• Some body sites remain sterile
• Stomach, blood, urine, CSF, tissues

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Beneficial Role of the IM

• Metabolic contributions production of vitamins
  during starvation (other animals more often)
  degrade bile salts, absorption of water and
  sodium in gut
• KEY competition for invading harmful microbes-
  colonization resistance
• Long term treatment with antibiotics reduced
  colonization resistance (reduces ID50)
• Psuedomembranous colitis cause by C. difficile

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Colonization Resistance

• Alters surface for adhesion of invaders
• Mutual growth inhibition
• Crowding, blocks binding sites
• Competition for essential nutrients
• Vitamins, amino acids, iron
• IM stimulates production of cross-reactive Abs
• Immune system priming
• Production of antibacterial products
• antibiotics and bacteriocins

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Detrimental Role of IM

• Physicians see more patients with disease due to
  IM than any other agent acquired outside the
  body. 30 of people that die in hospitals, die of
  IM opportunistic infections
• Conversion of lactose to fatty acids and CO2
• Lactose intolerance
• Cause opportunistic infections
• Route to sepsis (microbes in blood), usually gut
  IM
• Produce carcinogens? (microbial metabolic
  products) e.g. cyclamate (sweetener) which is
  converted into cyclohexamine by IM enzymes.

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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Mf
Phagocytosis
Light microscope
Transmission electron microscope
Scanning electron microscope
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Reactive oxygen intermediates and oxidative
burstssuper oxide, hydrogen peroxide,
hypochlorous acid, and nitric oxide
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MACROPHAGE
PMN (neutrophil)
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Evade/Inhibit Phagocytosis-first line of defense

• Antiphagocytic K. pnuemoniae, H. influenza, B.
  anthracis, E. coli, S. typhi) e.g. capsule, M
  protein
• Escape from phagosome (Legionella, Shigella,
  Rickettsia)
• Prevent phagosome-lysosome fusion (Mycobacterium,
  Legionella)
• Suicide bags (Streptococci haemolysins) (gtPMNs
  than macrophages) cytoplasm liquifies
• Fail to trigger oxidative burst (Mycobacterium,
  Legionella)
• Resist lysosomal degradation (Leishmania,
  Trypanosoma)
• Inhibit chemotaxis/locomotion of phagocyte (S.
  aureus, C. perfringens)

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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Induce Tolerance

• An immunologically specific reduction in the IR
  to a given antigen-raises risk
• Can involve both T cell or Antibody response
• Molecular mimicryclose to self, will not
  elicit IR. Ex receptor-ligand adhesion, capsule
  in Strep appears identical to connective tissue
• Desensitizationif large s of circulating Ab-Ag
  complexes are present, the intimate contact
  between lymphocytes and APCs is interrupted and
  anergy results (Treponema pallidium)
• Prenatal Infection If Ag is present during
  development, the IR may consider it self. (e.g.
  rubella virus). Mom provides IgG, and feotus
  makes IgM, but both weak. Can lead to clonal
  deletion.

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Examples of Mimicry
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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression/removal
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Immunosuppression/removal

• General immunosuppression prevention of the
  formation of an IR. E.g. HIV/AIDS. The virus
  infects immune cells. Loss of IR.
• Antigen-specific immunosuppression Suppress IR
  to a specific Ag of a microbe.
• During TB, the IR to TB-Ag is reduced, but normal
  responses exist to other bacterial Ags.
• Removal of Antibodies by soluble Ag
• Surface Ags are key ones to evoke Ab response.
  Soluble Ag is released during infection can soak
  up Abs, leaving microbe unharmed (Pseudomonas
  aeruginosa releases irs capsule during
  replication)

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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Hide or undergo variation

• Find an inaccessible niche (e.g. warts)
• Antigen variation (AV)periodically changing form
  of microbial antigens through mutation or
  recombination. (e.g. influenza virus,
  Trypanosoma, Strep pnuemoniae)
• Antigenic Driftarises from mutation
• Antigenic Shiftarises from recombination
• Phase Variation (PV) Genes alternate between on
  and off state in production of molecule(s) e.g
  allow adhesion when need it, motility when need
  it-ex. N. gonorrhea pilis production, S.
  typhimurium flagellar synthesis undergoes both AV
  and PV.
• Prevents development of vaccines

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Infection with Trypanosome
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Antigen Drift
Antigenic Shift
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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Induce the wrong immune response

• If antibodies are formed against unimportant Ag
  of a given microbe, will have only very weak
  infection control.
• Salmonella typhi bacterial infections controlled
  by T cells, but they make toxins that sway the IR
  to induce a humoral response
• Viruses where Abs are made to surface Ags that do
  not render them uninfectious, and these complexes
  can circulate as infectious (leukaemia virus in
  mice)

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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Produce toxigenic factors/tissue damage

• Product of microbe that produces disease
• k/o ability to produce toxin, no disease
• Endotoxins (lipopolysacchararides-LPS)
• All gram negative bacteria produce endotoxin as
  it comes directly from the cell wall and is toxic
  when released during division/death
• 2-part molecule, O antigen- polysaccharide
  (immunogenic) and lipid component (Lipid A)
• Binds to CD14 on Mf causing IL-1 release leading
  to fever, achiness and potentially shock (super
  antigen)
• Exotoxins produced by microbe -3 types

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Immunogenic portion
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Exotoxins

• Type 1 A-B toxins toxin is comprised of 2
  components. B is the binding moiety, A is the
  active moiety (toxin). V. Cholerae, Tetanus,
  Diptheria, Shigella, Anthracis. Acts by
  inhibiting or altering function of cell proteins
• Type 2 cell-membrane disrupting acts by pore
  formation. Staph. aureus, Anthracis
• Type 3 super antigens overstimulation of the
  immune response, including over production of
  cytokines (Staphyloccal toxic shock toxin)

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Action of A-B toxin
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Usual antigen shown in red
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Microbial Strategies

• Evade/Inhibit Phagocytosis
• Induce Tolerance
• Immunosuppression
• Hide or undergo antigenic/phase variation
• Induce the wrong immune response
• Produce toxigenic factors
• -Two outcomes Persistence and latency

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Persistence and latency

• Usually follows a primary, acute infection
• Creation of carriers (asymptomatic people that
  harbor a pathogen and spread w/out knowledge)
• Recovery-relapse cycle
• Usually does not cause lethal disease
• Immune response cannot clear infection
• Persistence- with shedding microbes can be found
  continuously in person (e.g. IM, H. pylori)-
  sustains disease in community
• Persistence without shedding- latency cant
  isolate microbe. usually viruses, TB

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TuberculosisgranulomaformationSolid
Granuloma,small (lt 3mm) usually successfulin
containingbacteria-latency
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Table

• IRimmune response
• IMindigenous microflora
• Agantigen
• Abantibodies
• PMNpolymorphonuclear cells
• Mfmacrophage
• lipopolysacchararides-LPS
• k/o create a disrupted gene strain (knockout)
• APCs antigen presenting cells