Lecture 5 BIOL 533 1
Constitutive Defenses of the Host
BIOL 533
Lecture 5
Medical Microbiology
Lecture 5 BIOL 533 2
Constitutive Defenses
? Barriers to entry
– See Schaechter text,Table 6.1
? Mucous membranes—covered by
protective layer of mucus
– Mechanical and chemical barrier that allows
proper functioning
? Cross-linked gel structure composed of
glycoprotein subunits
Lecture 5 BIOL 533 3
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
Lecture 5 BIOL 533 4
Defenses of Deep Tissues
? Role of constitutive defenses
– List of humoral mediators of constitutive
defenses (See Schaechter text,Table 6.2)
Lecture 5 BIOL 533 5
Defenses of Deep Tissues
? Role of constitutive defenses,cont’d,
– 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
Lecture 5 BIOL 533 6
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
Lecture 5 BIOL 533 7
Inflammation
? General aspects
– Reaction to tissue injury—manifested 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
Lecture 5 BIOL 533 8
Inflammation
? Tissues may return to normal or scarring
may result; depends on extent of damage
done,
– By injury
– By infecting microbes
– By inflammatory response
Lecture 5 BIOL 533 9
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 acid—antimicrobial
Lecture 5 BIOL 533 10
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
Lecture 5 BIOL 533 11
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
Lecture 5 BIOL 533 12
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
Lecture 5 BIOL 533 13
Molecular Basis
? Kinin—small basic peptides
– Alter vascular tone
– Increase permeability
– May initiate or potentiate release of other
chemical mediators from leukocytes
? Bradykinin is best-known
Lecture 5 BIOL 533 14
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
Lecture 5 BIOL 533 15
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
Lecture 5 BIOL 533 16
Molecular Basis
? Aspirin prevents both synthesis and
effects of prostaglandins
? Fever provides,
– Important warning sign of infection
– Interference with antimicrobial mechanism
Lecture 5 BIOL 533 17
Mechanism of Inflammation
? Injured tissue cells release inflammatory
mediators that activate inner lining
(endothelium) of capillaries
Lecture 5 BIOL 533 18
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
Lecture 5 BIOL 533 19
Mechanism of Inflammation
? Encounter inflammatory activators
– Integrins on neutrophils (adhesion receptors)
– Attach to endothelial receptors
? ICAM1—intracellular cell adhesion
molecule
? VCAM—vascular adhesion molecule
Lecture 5 BIOL 533 20
Mechanism of Inflammation
? Neutrophils stick to endothelium and stop
moving
– Undergo dramatic shape changes; migrate
through wall into tissue space
Lecture 5 BIOL 533 21
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
Lecture 5 BIOL 533 22
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 Ca+2)
degranulation; release of preformed
mediators histamine
Lecture 5 BIOL 533 23
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
Lecture 5 BIOL 533 24
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
Lecture 5 BIOL 533 25
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)
Lecture 5 BIOL 533 26
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
Lecture 5 BIOL 533 27
Inflammation
? Acute phase response—during
inflammation,certain proteins are released
(chiefly from the liver) and their
concentration rises in sera
Lecture 5 BIOL 533 28
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
Lecture 5 BIOL 533 29
Acute Phase Response
? Different functions
– C-reactive protein—enhances inflammatory
response by activating complement
–?1-antitrypsin—inhibits proteases that
function in inflammation
Lecture 5 BIOL 533 30
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 response—proteins
(cytokines) formed by ―activated
monocytes‖
Lecture 5 BIOL 533 31
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
Lecture 5 BIOL 533 32
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)
Lecture 5 BIOL 533 33
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
Lecture 5 BIOL 533 34
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
Lecture 5 BIOL 533 35
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
Lecture 5 BIOL 533 36
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
Lecture 5 BIOL 533 37
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
Lecture 5 BIOL 533 38
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
Lecture 5 BIOL 533 39
Role of Complement
? Responsible for lysis of,
– Bacteria
– Some viruses
– Foreign cells
– Can even lyse foreign cells with membranes
containing viral protein
Lecture 5 BIOL 533 40
Role of Complement
? Mechanism of lysis—carried 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
Lecture 5 BIOL 533 41
Role of Complement
? Induces inflammatory response via
formation of interleukin-1,TNF,and
anaphylatoxins
? Beneficial,inflammatory response helps
fight invading microbes
Lecture 5 BIOL 533 42
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
Lecture 5 BIOL 533 43
Lecture 5
? Questions?
? Comments?
? Assignments..,
Constitutive Defenses of the Host
BIOL 533
Lecture 5
Medical Microbiology
Lecture 5 BIOL 533 2
Constitutive Defenses
? Barriers to entry
– See Schaechter text,Table 6.1
? Mucous membranes—covered by
protective layer of mucus
– Mechanical and chemical barrier that allows
proper functioning
? Cross-linked gel structure composed of
glycoprotein subunits
Lecture 5 BIOL 533 3
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
Lecture 5 BIOL 533 4
Defenses of Deep Tissues
? Role of constitutive defenses
– List of humoral mediators of constitutive
defenses (See Schaechter text,Table 6.2)
Lecture 5 BIOL 533 5
Defenses of Deep Tissues
? Role of constitutive defenses,cont’d,
– 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
Lecture 5 BIOL 533 6
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
Lecture 5 BIOL 533 7
Inflammation
? General aspects
– Reaction to tissue injury—manifested 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
Lecture 5 BIOL 533 8
Inflammation
? Tissues may return to normal or scarring
may result; depends on extent of damage
done,
– By injury
– By infecting microbes
– By inflammatory response
Lecture 5 BIOL 533 9
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 acid—antimicrobial
Lecture 5 BIOL 533 10
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
Lecture 5 BIOL 533 11
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
Lecture 5 BIOL 533 12
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
Lecture 5 BIOL 533 13
Molecular Basis
? Kinin—small basic peptides
– Alter vascular tone
– Increase permeability
– May initiate or potentiate release of other
chemical mediators from leukocytes
? Bradykinin is best-known
Lecture 5 BIOL 533 14
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
Lecture 5 BIOL 533 15
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
Lecture 5 BIOL 533 16
Molecular Basis
? Aspirin prevents both synthesis and
effects of prostaglandins
? Fever provides,
– Important warning sign of infection
– Interference with antimicrobial mechanism
Lecture 5 BIOL 533 17
Mechanism of Inflammation
? Injured tissue cells release inflammatory
mediators that activate inner lining
(endothelium) of capillaries
Lecture 5 BIOL 533 18
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
Lecture 5 BIOL 533 19
Mechanism of Inflammation
? Encounter inflammatory activators
– Integrins on neutrophils (adhesion receptors)
– Attach to endothelial receptors
? ICAM1—intracellular cell adhesion
molecule
? VCAM—vascular adhesion molecule
Lecture 5 BIOL 533 20
Mechanism of Inflammation
? Neutrophils stick to endothelium and stop
moving
– Undergo dramatic shape changes; migrate
through wall into tissue space
Lecture 5 BIOL 533 21
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
Lecture 5 BIOL 533 22
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 Ca+2)
degranulation; release of preformed
mediators histamine
Lecture 5 BIOL 533 23
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
Lecture 5 BIOL 533 24
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
Lecture 5 BIOL 533 25
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)
Lecture 5 BIOL 533 26
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
Lecture 5 BIOL 533 27
Inflammation
? Acute phase response—during
inflammation,certain proteins are released
(chiefly from the liver) and their
concentration rises in sera
Lecture 5 BIOL 533 28
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
Lecture 5 BIOL 533 29
Acute Phase Response
? Different functions
– C-reactive protein—enhances inflammatory
response by activating complement
–?1-antitrypsin—inhibits proteases that
function in inflammation
Lecture 5 BIOL 533 30
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 response—proteins
(cytokines) formed by ―activated
monocytes‖
Lecture 5 BIOL 533 31
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
Lecture 5 BIOL 533 32
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)
Lecture 5 BIOL 533 33
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
Lecture 5 BIOL 533 34
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
Lecture 5 BIOL 533 35
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
Lecture 5 BIOL 533 36
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
Lecture 5 BIOL 533 37
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
Lecture 5 BIOL 533 38
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
Lecture 5 BIOL 533 39
Role of Complement
? Responsible for lysis of,
– Bacteria
– Some viruses
– Foreign cells
– Can even lyse foreign cells with membranes
containing viral protein
Lecture 5 BIOL 533 40
Role of Complement
? Mechanism of lysis—carried 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
Lecture 5 BIOL 533 41
Role of Complement
? Induces inflammatory response via
formation of interleukin-1,TNF,and
anaphylatoxins
? Beneficial,inflammatory response helps
fight invading microbes
Lecture 5 BIOL 533 42
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
Lecture 5 BIOL 533 43
Lecture 5
? Questions?
? Comments?
? Assignments..,
