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Attachment of sialic acid (and other substances) to _______________ prevents formation of C3 convertase.
LPS O-antigen
(changes in length of LPS O-antigen side chains prevent effective MAC formation.)
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Bacteria can coat themselves with antibodies! What are the 2 examples?
S. aureus - protein A
Step. pyogenes - protein G
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C3 convertase functions
- C3a - vasodilator
- C3b - opsonization
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What are the functions for C5a ?
vasodilator and attracts phagocytes
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What are the functions for C5b ?
helps recruits proteins to form the MAC
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What are the 3 strategies that prevent migration of phagocytes to site of infection?
-bacteria produce enzymes that degrade C5a (chemoattractant for phagocytes) found in Gram (+)
toxin produced to kill phagocytes, inhibit migration/ reduce oxidative burst.
modification of LPS, do immune response is not activated ex: H. pylori
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Surviving Phagocytosis:
ability to survive inside cells that include PMNs, macrophages, etc have made intracellular pathogens some of the most dangerous to man.
Bacteria hide inside host cells and avoid host immune system
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Some pathogens have developed mechanisms to overcome protective cells...
action against the toxic oxygen radicals
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Example of action against toxic oxygen radicals (about inhibition of phagocytes)
Sty. aureus produces pigmented cmpds aka carotenoids neutralize "oxidative burst"
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Example of action against toxic oxygen radicals (about inhibition of phagocytes)
Mycobacterium tuberculosis - intracellular pathogens uses cell wall glycolipids to scavenge toxic oxygen cmpds. Removes hydroxyl radicals and superoxide anions.
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Inhibition of Phagocytes
1. action against toxic oxygen radicals
2. Leukocidins -cytotoxin
3. Capsule
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Leukocidine(cytotoxin) are produced by some intracellular pathogens such as...
Stap. aureus and Step. pyogenes
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Dead phagocytes make up a large put of ....
pus
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What is a pus-forming bacteria?
pyogenic
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Encapsulated bacteria are often highly resistant to phagocytosis and capsule prevents adherence of phagocyte to bacterial cell, what is an example?
10 cells can kill a mouse in a few days ; NON-encapsulated strains are avirulent.
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What is an example of a bacteria that's capsulated?
Step. pneumoniae
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What are capsules made up of ?
polsaccharide / protein coating
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Encapsulated bacteria are often highly resistant to what?
phagocytosis (a process when a cell engulfs a solid particle to form an internal vesicle aka phagosome.)
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Phagocytes are excellent killers essential for clearing invading bacteria from an infected area but must be kept under ________ _____________.
tight control
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What is pus mainly composed of ?
DNA
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Cytokines/chemokines and complement guide the phagocytes to the infection. These cells are primed for activation only at .. ?
the site of infection.
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Cytokines are involved in.... ?
cell signaling.
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List of Cytokines
chemokines
interferons
interleukins
lymphokines
tumour necrosis factor
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Immune cells like macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells and fibroblasts all produce what?
cell signaling!
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Nitric Oxide (NO) is a ... ?
very versatile cmpd!
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During an infection cytokines trigger monocytes and macrophages to produce _____________.
Nitric Oxide (NO)
-which attacks bacterial metalloenzymes, proteins, and DNA.
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What is peroxynitrite ?
a reactive molecule that oxidizes amino acids (disrupt the conformation causing proteins to denature).
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How is peroxynitrite formed?
-synergy of nitric oxide (NO) combined with superoxide.
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NO is toxic to __________ and _________ cells .
bacteria and human
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Inflammation is ?
a non-specific rxn to noxious(poisonous) stimuli such as toxins and pathogens -redness, swelling and pain.
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inflammation is mediated by ....
cytokines!
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Interleukins are .....
Interleukins are a group of cytokines The term interleukin derives from (inter-) "as a means of communication", and (-leukin) "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes".
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Inflammation may be caused by externally induced pyrogenic agents from ______________ or ____________ released from leukocytes.
(LPS) (fever inducing / heat generating) or endogenous pyrogens released from leukocytes.
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What is a continuous fever?
body temp remains elevated over 23 hr period; <1°C variation.
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What is intermittent fever?
body temp shifts btwn normal and raised thruout 24 hrs period; characteristic of most infectious diseases.
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What is relapsing fever?
fever returning after an infection is reestablished.
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Signs of inflammation:
- swelling
- redness
- pain
- heat
- loss of function
**signs are due to changes in blood vessel function
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Goals of inflammation:
to bring phagocytes to injured area to:
- isolate, destroy, inactivate invader
- remove debris
- prepare subsequent healing
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Stages of inflammation:
1. Phagocytosis by macrophages
2. Dilation and increased permeability
3. Containment of bacteria and foreign matter
4. Leukocyte proliferation and migration
5. Continues acitivty of recruited leukocytes
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) trigger....
release of monocytes and PMNs (polymorphonuclear leukocytes/neutrophiles) 4rm bone marrow onto circulation.
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which cytokines up-regulate host reponses and stimulate the killing active of PMNs?
- cytokines -IL-1, IL-6 (interleukins)
- Tumor Necrosis Factor (TNF-α)
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IL-1, interferon and TNF-α stimulate endothelial cells to do what ?
produce selectins that bind loosely to the surface of PMNs and other cells causing them to slow.
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IL8 (cytokine) stimulate PMNs to produce intergrins that in turn stimulate more cytokines called
intracellular adhesion molecules (ICAMS) to generate a tighter attachment of above cells (Marginations).
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PMNs stop and flatten against the vessel wall and force themselves btwn the endothelial cells into deeper tissues. This method is called?
Transmigration
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Platelet-endothelial cell adhesion molecule (PECAM) assists...?
Transmigration (when PMNs stop and flatten against the vessel wall and force themselves btwn the endothelial cells into the deeper tissue)
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IL-1, IL-8, TNF-α and platelet activating factor (PAF) activate ... ?
PMNs oxidative burst enabling the full killing capacity of the cell.
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What is margination?
slowing and stopping of polymorphonuclear leukocytes (PMNs)
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What are toll-like receptors ?
a set of pattern recognition molecules found on surface of phagocytes for LPS
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What do PAMPs (Pathogen-Associated Molecular Patterns) do ?
they recognize structures on bacteria.
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What does LBP stand for and what does it do?
- Lipopolysaccharide Binding Protein
- produced by hepatocyte intestinal epithelial cells - circulates in serum.
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What are the 3 reasons of how is inflammation a defense mechanism?
(physical symptoms: redness, swelling, pain, heat, etc)
- expansion of capillaries to increase blood flow
- increase in permeability of microvascular structures to allow escape of fluid
- exit of leukocytes from the capillaries and response to infection (pus)
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When (if) the phagocytes are successful in eliminating the invading bacterium, a 2nd set of cytokines begin to predominate...What are they?
IL-4, IL-10, and IL-13 down-regulate production of TNF-α and reduce killing activities of phagocytes and returning the system to its normal inactive level.
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Cytokines have a major control on inflammation by stimulating the ___________ _________ killing action
oxidative burst
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IL-1, Il6, IL-8, platelet activating factor (PAF) and TNF-α (killing action of phagocytes) are examples of... ?
Proninflammatory cytokines
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IL-4, IL-10, and IL13 are examples of ... ?
Anti-inflammaotry cytokines
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The most common Gram (-) form of pathogen that causes septic shock
Gram (-) Salmonella or E.coli : ruptured or leaking bowel releasing organisms into the intra-peritoneal cavity or the bloodstream.
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The most common Gram (+) form of pathogen that causes septic shock
Staphylococcus aureus and Streptococcus pyogenes : burns
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The Gram (-) and Gram (+) pathogens that causes septic shock produces....
endotoxins
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Septic shock occurs in 4 stages:
- 1. Systemic inflammatory response syndrome (SIRS): Temps over 38°C or under 36°C. Higher heart and respiratory rates. Unusually high or low neutrophil count.
- 2. Sepsis: SIRS with a culture positive laboratory result.
- 3. Severe sepsis: Organ dysfunction and very low blood pressure.
- 4. Septic shock: very low blood pressure despite fluid administration.
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What occurs in stage 1 of Septic shock (Systemic inflammatory response syndrome) ?
Temps over 38°C or under 36°C. Higher heart and respiratory rates. Unusually high or low neutrophil count
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What occurs in stage 2 of Septic shock (sepsis) ?
SIRS with a culture positive laboratory result
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What occurs in stage 3 of septic shock (severe sepsis) ?
Organ dysfunction and very low blood pressure.
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What occurs in stage 4 of septic shock (septic shock) ?
very low blood pressure despite fluid administration
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Septic Shock leads to...
-essential organs deny oxygen and nutrients resulting failure of kidneys, ♡, brain, and lungs [Multiple Organ Dysfunction (Failure)] = death
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Out of control inflammation can be possible because...
- Phagocytes cause cell lysis and products spreads though blood– LPS
- Release of inflammatory cytokines
- Induction of prostaglandins –variety of actions (from brain)
- These pyrogens causes uncontrollable high fever, increased vascular permeability causes massive efflux of fluids from central vascular tissue.
- Antibiotics can actually accelerate this!? Cell lysis –releases LPS
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The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects(10 known pro. receptors). It can cause...
- constriction or dilation in vascular smooth muscle cells
- cause aggregation or disaggregation of platelets
- sensitize spinal neurons to pain
- regulate inflammatory mediation
- control cell growth
- (regulate calcium movement, control hormone regulation)
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Disseminated intravascular coagulation (DIC) is ....
clots plug capillaries and seen as blackish or reddish skin lesions
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Intracellular Pathogens are...
specialized group of pathogens, some are obligately parasitic; normally functional genes are not required as host cell provides all nutrients... reduction in genome size
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Size of E.coli
4 million bp w/ 3000 genes
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Size of M. pneumoniae ..
0.5-0.8 Mbp
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Chlamydiae pneumoniae and C. trachomatis size
1Mbp
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Salmonella typhimurium is an example of a pathogen that can survive within macrophages...
- survive within modified phagosomes.
- delay acidification of the phagosome.
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Mycobacterium tuberculosis
- prevent phagosome maturation
- delay acidification of the phagosome.
- capable of persisting within macrophages for the life of the host
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Listeria monocytogenes
- escape the activated phagosomereplicate within the macrophage cytoplasm
- cell to cell transfer to other uninfected macrophages
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What happens during entry into phagocytes? (entry of bacteria into host cell)
- bacteria are ingested and 4rm the phagosome, however the fusion with lysosome (containing toxic substances) is blocked.
- Legionella pneumophila,
- Mycobacterium tuberculosis, and
- Salmonella typhimurium.
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What happens to non-phagocytic cells...
- invasins (bacterial surface proteins) causes polymerization and depolymerization of actin that form and mediate the cytoskeleton producing pseudopodia-like structures that mediate engulfment of the bacterium.
- ex: Shigella enterica
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Other invasive pathogens can...
- disrupt the surrounding vacuole membrane and escape into the cytoplasm
- multiply and move about by directing local actin polymerization at one end of the bacterium, a process called ‘actin-based motility’
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