Constitutive Defenses of the Host

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Constitutive Defenses of the Host
Medical Microbiology

• BIOL 533
• Lecture 5

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Constitutive Defenses

• Barriers to entry
• See Schaechter text, Table 6.1
• Mucous membranescovered by protective layer of
  mucus
• Mechanical and chemical barrier that allows
  proper functioning
• Cross-linked gel structure composed of
  glycoprotein subunits

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Mucus Membranes

• Entraps particles and prevents them from getting
  to mucus membrane
• Hydrophilic allows passage of a number of bodily
  substances
• Antimicrobial substances (lysozyme and
  peroxidase)
• Can withstand substantial weight, but still be
  propelled by cilia

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Defenses of Deep Tissues

• Role of constitutive defenses
• List of humoral mediators of constitutive
  defenses (See Schaechter text, Table 6.2)

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Defenses of Deep Tissues

• Role of constitutive defenses, contd.
• Inflammatory response does not require previous
  contact with microorganism
• Elicited by complex effectors, many of which are
  complement system
• Normally at basal level and must be further
  increased by presence of microorganisms in
  tissues
• Most important consequence of activity is
  phagocyte attraction

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Defenses of Deep Tissues

• Interaction of constitutive (inflammatory
  response) and inducible defenses (immune
  response)
• Inducible response cannot occur without
  constitutive mediators
• Mediators lead to induction of immune response
  and also defend against microbial invader

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Inflammation

• General aspects
• Reaction to tissue injurymanifested by pain,
  swelling, heat, and throbbing of location
• Location appears red and shiny, hot and painful
  to touch as a result of changes in local blood
  vessels and lymphatics
• Tissues may return to normal or scarring may
  result

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Inflammation

• Tissues may return to normal or scarring may
  result depends on extent of damage done
• By injury
• By infecting microbes
• By inflammatory response

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Inflammation

• Description of changes
• Blood supply increases to affected part due to
  vasodilation
• Capillaries become more permeable, allowing fluid
  and large molecules to move into tissues
• Consequence of inflammation
• pH of inflamed tissues lowered
• Production of lactic acidantimicrobial

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Inflammation

• Molecular basis of inflammatory response and
  acute phase response
• Inflammatory response starts with activation of
  complement or of blood-clotting cascade
• Complement and clotting are interactive
• Either can set off the other
• Normally, clotting is seen when acute
  inflammatory response is severe

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Molecular Basis

• Inflammatory response leads to production and
  release of a number of chemical effectors of
  inflammation responsible for vascular
  permeability, vasodilation, and pain
• Histamine
• Kinin
• Leukotrienes and prostaglandins

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Molecular Basis

• Histamine is one of best-known
• Dilates blood vessels and increases permeability
• Mechanism of production
• Three peptides (C3a, C4a, and C5a
  anaphylotoxins) produced by activation of
  complement system
• Stimulate release of histamine from mast cells

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Molecular Basis

• Kininsmall basic peptides
• Alter vascular tone
• Increase permeability
• May initiate or potentiate release of other
  chemical mediators from leukocytes
• Bradykinin is best-known

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Molecular Basis

• Production of kinins
• Hageman factor activated during inflammation (one
  of substances that can activate is LPS)
• Induces production of kinins
• Also plays important role in blood coagulation
• Cleavage of precursor kininogens activated by
  enzymes (kallikreins) produced during clotting
  cascade or release from granulocytes

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Molecular Basis

• Leukotrienes and prostaglandins
• Act on motility and metabolism of wbc
• Two plus certain phospholipids cause aggregation
  of blood platelets (important to stop bleeding)
• Prostaglandins synthesized in hypothalamus act on
  temperature regulatory centers of brain and cause
  fever

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Molecular Basis

• Aspirin prevents both synthesis and effects of
  prostaglandins
• Fever provides
• Important warning sign of infection
• Interference with antimicrobial mechanism

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Mechanism of Inflammation

• Injured tissue cells release inflammatory
  mediators that activate inner lining
  (endothelium) of capillaries

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Mechanism of Inflammation

• Within capillaries, selectins (cell adhesion
  molecules) Psel then Esel
• Randomly attract and attach neutrophils
• Slow them down cause to move through capillaries

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Mechanism of Inflammation

• Encounter inflammatory activators
• Integrins on neutrophils (adhesion receptors)
• Attach to endothelial receptors
• ICAM1intracellular cell adhesion molecule
• VCAMvascular adhesion molecule

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Mechanism of Inflammation

• Neutrophils stick to endothelium and stop moving
• Undergo dramatic shape changes migrate through
  wall into tissue space

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Mechanism of Inflammation

• Inflammatory mediators released by injured tissue
  also raise acidity in extracellular fluid
• Decrease in pH activates extracellular enzyme
  kallikrein splits bradykin from precursor

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Mechanism of Inflammation

• Bradykin binds to receptors on capillary wall,
  opening junctions between cells allows
  leukocytes and fluid into tissues
• Also, simultaneously binds to mast cells in
  connective tissue
• Activates mast cells (by influx Ca2)
  degranulation release of preformed mediators
  histamine

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Mechanism of Inflammation

• If nerves damaged, they release substance P also
  bind to mast cells, increasing preformed mediator
  release
• Histamine makes intercellular junctions in
  capillary wall wider, so more fluid, leukocytes,
  kallikrein, and bradykinin precursors move out,
  causing edema

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Mechanism of Inflammation

• Bradykinin then binds to nearby capillary cells
  and stimulates production of prostaglandins PGE2
  and PGE2?, causing tissue swelling
• Prostaglandins also bind to nerve endings,
  causing pain

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Mechanism of Inflammation

• Change in mast cell plasma membrane permeability
  allows phospholipase A2 to be converted to
  arachidonic acid
• Arachidonic acid proceeds through cyclo-
  oxygenase pathway -OR- lipoxygenase pathway
  (depends on mast cell type)

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Mechanism of Inflammation

• Pathways yield synthesized mediators
• Prostaglandin E2 F2?
• Thromboxane A2
• Slow-reacting substance
• Leukotrienes
• See Prescott, Fig. 29.13 Biochemical
  Effects of Inflammation

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Inflammation

• Acute phase responseduring inflammation, certain
  proteins are released (chiefly from the liver)
  and their concentration rises in sera

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Acute Phase Response

• Rise in sera is disproportionate
• C-reactive protein (reacts with C polysaccharide
  of pneumococci and other bacterial Ag) and serum
  amyloid A protein increase 1000 times or more
• ?1-antitrypsin and complement factor B increase
  by 2 or 3 fold

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Acute Phase Response

• Different functions
• C-reactive proteinenhances inflammatory response
  by activating complement
• ?1-antitrypsininhibits proteases that function
  in inflammation

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Acute Phase Response

• Other important proteins released
• Those that avidly bind iron and other metals
• Reduces availability of required ions for
  microorganisms
• Helps inhibit microbe growth
• Induction of responseproteins (cytokines) formed
  by activated monocytes

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Induction of Response

• Interleukin-1 (IL-1) endogenous pyrogen
• Causes fever by stimulating prostaglandins
• Stimulates proliferation of cells involved in
  immune response
• Enhances stickiness of inside surface of
  endothelial cells in capillaries to neutrophils
• Facilitate movement to particular area

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Induction of Response

• Tumor necrosis factor (TNF cachectin)
• Has antitumor activity
• Causes weight loss (severe problem in certain
  chronic infections, such as tuberculosis and some
  cancers)

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Induction of Response

• Characteristics of both IL-1 and TNF
• Play major role in shock response elicited
  during some serious bacterial infections
• Both made in response to presence of
  microorganisms

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Induction of Response

• Other important cytokines
• Interleukin-2
• Involved in proliferation of immunologically
  important cells
• Used therapeutically to treat certain tumors
• Interleukin-6 (hepatocyte-stimulating factor)
• Involved in synthesis of acute phase response
  proteins by the liver

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Complement

• General characteristics
• Comprises as many as 26 proteins found in sera
  and some as a part of cell membranes
• Mediates large number of biological effects
• Interacts with other complex systems, including
• Blood-clotting
• Specific immune response

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Complement

• Normally present at basal level
• When activated, enhances antimicrobial defenses
• Making intruding bacteria susceptible to
  phagocytosis
• Causing lysis of bacteria
• Producing chemotactic substances
• Promoting inflammatory response

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Complement

• Activation (proteolytic cleavage of precursor) in
  one of two ways that produce same end products
• Classical pathway activated by presence of
  Ag-Ab complexes
• Alternative pathway independent of Ab
  elicited by bacterial surface components, such as
  LPS

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Role of Complement

• In patient studies, patients genetically lacking
  some of complement components are very
  susceptible to bacterial diseases (some
  life-threatening)
• Enhancing phagocytosis
• Recruitment of wbc by chemotactic protein
• Facilitation by proteins called opsonins

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Role of Complement

• Responsible for lysis of
• Bacteria
• Some viruses
• Foreign cells
• Can even lyse foreign cells with membranes
  containing viral protein

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Role of Complement

• Mechanism of lysiscarried out by membrane attack
  complex
• Inserts itself into membranes and alters their
  permeability
• Particularly important with bacteria that have
  resistance mechanisms against phagocytosis
• Neisseria (gonorrhea) streptococci (meningitis)
• Patients with genetic deficiencies for mak
  components very susceptible to these diseases

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Role of Complement

• Induces inflammatory response via formation of
  interleukin-1, TNF, and anaphylatoxins
• Beneficial inflammatory response helps fight
  invading microbes

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Role of Complement

• Negative in patients with hypersensitivity
  disorders, inflammatory response damages
  sensitive tissue
• Cause leukocytes to secrete lysosomal enzymes
• Diseases include rheumatoid arthritis, serum
  sickness, and infective endocarditis

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Lecture 5

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