3 damage Flashcards
bug mediated mech of damage
- intoxication
- growth outside normal niche
- overgrowth in normal niche
collaborative mechanisms of damage
- growth inside host cells
- lytic enzymes
- toxin mediated
- cytokine release
host mediated mechanisms of damage
- inflammation
- immune complex deposition
- autoimmunity
pseudomonas elastase
enters tissue, chews up elastin, disseminates
-bacterial mediated virulence factor
what does elastase chew up
- collagen
- lysozyme
- C3b + C5b (affects immune system)
ECM
- collagen
- elastin
- hyaluronic acid
example of bacterial mediated factor
elastase from pseudomonas
how does elastase help pseudomaonas
helps it get access to cells and disseminate
strains lacking in elastase
persist locally in burn wounds but fail to disseminate
how is elastase a multitasking enzyme
cleaves elastin, collagen, lysozyme, immunoglobulins, and complements C3B + C5a (inhibits opsonization + chemotactic responses)
plasmin
chews up fibrins/clots
borelia
retains ability to bind so that plasminogen can make plasmin + eat clots
neutrophils
elastase allows it to get into the tissue
-psuedomonas deactivates normal neutrophil elastase, allowing plasminogen to plasmin, and then there’s an attack of the host
examples of enzymatic virulence factors that are more “collaborative” involve
borrelia hurgdorferi + yesinia pestis
nontoxin mediated damage
bug mediated pseudomonas elastase + lytic enzymes
non-toxin-mediated damages
collaborative + bug mediated
what facilitates borrelia bind human plasminogen and its activator?
spirochetes
What does activated plasminogen do?
converts plasminogen to palasmin
plasmin
protease that breaks down fibrin clots, eliminating fibrin barriers at wound sites
fibrin
protein that form clots during microbial invasion which is triggered by tissue injury
pathogens counter fibrin by producing
fibrinolytic enzymes OR subverting host enzymes that dissolve the clots making further dissemination possible
dissemination
the act of spreading something, especially information, widely; circulation.
Yersinia Pestis
has a pla gene (plasmin activator gene) which has protease activity on its own + can activate host plasmin
pla gene
plasmin activator gene from Yersinia Pestis
strep pyogenes (collaborative)
makes streptokinase, which binds to and activates plasminogen, converting it to plasmin
staph aureus (collaborative)
produces fibrinolysin and a coagulase that lays down a fibrin network that may provide a protected niche
what produces hyaluronidase?
strep, staph + clostridia
hyaluronic acid
ECM structural component
what causes gas gangrene?
clostridia
what does clostridia produce?
collagenase, which breaks down tissue supporting collagen matrix, enhancing spread throughout the body
what do enzymatic virulence factors that bacteria make, do?
degrade proteins or carbs that maintain tissue integrity, allowing enhanced dissemination
lytic enzymes that are multifunctional
modulate immune function
-elastase acting on Ig, C3b, C5a
bug mediated growth outside normal niche can occur during
dental treatment
bug mediated overgrowth in normal niche occurs with what two organisms?
D. Difficile + candida albicans
What collaborative mechanism of damage involves growth inside host cells?
tuberculosis (inside has access to nutrients)
lytic enzymes collaborative mechanism of damage
macrophages cause lysis
Dental work
- growth outside normal nice
- leads to transient bacteremia, allowing viridans group streptococci to damage heart valves
surgery or trauma can lead to
spillage of intestinal contents into peritoneal cavity and subseueny abcess formation by bacteroids fragilis
overgrowth in normal niche can lead to
antibiotic therapy can lead to overgrowth of C. difficile in the GI tract and fungus candida albicans on mucosal surfaces
when macrophages are infected by mycobacterium
lysosomes leak and cause cellular damage with granulomas
growth inside cells
- mycobacterium tuberculosis
- legionella pneumophila
- salmonella typhii
tuberculosis
- survive in alveolar macrophages
- when macrophages are killed by intracellular bacteria, the lysozomal enzymes and other material released from dying cells contribute to chronic infection and granuloma formation
legionella pneumophila
survive in alveolar macrophages, subvery normal phagocytic pathway
salmonella typhii (typhoid mary)
gall bladder infection (asymptomatic carrier) that sheds bacteria into the intestinal tract and feces
after patient is exposed to broad spectrum antibiotics
pseudomembranous colitis
granuloma formation
- macrophage eats bug
- bug replicates
- cell lysis
- activated macrophages and T cells recruited walling off of bugs and cell debris
persistent infections induce persistant immune responses which in addition to failing to eliminate the infectious microorganism
cause pathological changes
old thinking granuloma
was hosts means of walling off bacteria
new thinking granuloma
bacteria induce granuloma to recruit naive macrophages they can then use for dissemination
immune complex deposition e.g. post streptococcal glomerulonephritis
1 strep infection is presented
2 anti strep antibody formation
3immune complex formation (antibody + strep fragments + complements)
4 immune complex deposition in glomeruli, leading to inflammation and kidney disfunction= BAD
what can lead to glomerulonephritis
microbial antigen in blood that lead to an immune complex function, leading to pathological changes
what is the major disease process that leads to glomerulonephritis?
immune complex formation
glomerulonephritis
painful kidney disease
strep pyogenes
group A strep/ strep throat
what complexes form in the bloodstream during strep throat
streptococcal Ag-Ab complexes that lodge in the glomeruli, causing inflammation of the kideny
glomeruli
filtration membranes of kidneys
nephritis
inflammation of the kidney
diseases that cause infection triggered autoimunity
strep + lyme disease
infection triggered autoimmunity
1 infection
2 generation of immune response against pathogen copmonents
2 cross reactivity against self antigens
how do autoimmune disorders occur from microbial infections?
microbial products somehow alter or unmask self components OR modulate the processes that normally maintain tolerance to self components
what helps in microbial evasion
similarities between microbial molecules (often surface) + host molecules
-the host immune response instead of protecting, elicits cross reactivity
autoimunity
rheumatic fever
scarlet fever
lyme disease
toxin
a protein that kills or alters the function of a host cell
exotoxin
a toxin that is secreted into the extracellular milieu by the bacteria
enterotoxin
a toxin that works in or is produced in the GI tract
endotoxin
the lipopolysaccharide component of the gram-negative outer membrane; NOT a true toxin
enterotoxin
an exotoxin that acts on the small intestine causing changes in intestinal permeability that lead to diarrhea
endotoxin
we will not consider this a true toxin
what causes death through hemorrhagic shock and tissue necrosis?
endotoxin= lipid A portion of LPS in large enough doses
pyrogens
endotoxin stimulates host cells to release proteins called pyrogens (cause fever)
medical supplies that are non-pyrogenic indicate
no LPS contamination
which toxicity is higher: endotoxins or exotoxins?
exotoxin
toxin that kill cells
streptolysin O +diphtheria toxin
toxin that act at cell surface
streptolysin O
toxin that act inside cells
diptheria toxin
toxin that disrupt function
toxic shock syndrome toxin (does NOT KILL cell)
+ cholera toxin (type AB toxin)
streptolysin O kills cells at the surface
a pore former toxin that binds to cholesteral in host membrane and forms pores upon oligimerization
diptheria toxin kills cells and act inside cells
A/B toxin (single polypeptide) that ADP ribosylates host EF2, stopping protein synthesis
staph aureus= disrupts cell physiology/function and act at cell surface
TSST-1 (Toxic shock syndrome)
- strep pryogenes, streptococcal pyrogenic exotoxins such as SPE A.
- specific for T cells
cholera toxin = disrupts cell physiology/function and act inside cells
A/B toxin with A/B (5) structure, B part binds GM1 ganglioside and A part acts in cells
-CT leads to increased intracellular cAMP, ion loss to gut lumen and poor ion uptake, rice water diarrhea
roles of toxins
- promote bacterial growth
- facilitate dissemination
- interfere with host defenses
how to do toxins promote bacterial growth?
by providing access to nutrients sequestered inside host cells
how do toxins facilitate dissemination
by breaking down epithelial carriers
how do toxins interfere with host defenses
by disrupting actin function in phagocytic cells
mechanisms for being active at cell surface
- pore formation
- phospholipase (chew through phospholipids)
- superantigen
- lysins
examples of pore formers
aerolysin, staph alpha toxin, streptolysin, listeriolysin O
examples of phospholipase
C perfingens alpha
examples of superantigen
staph TSST
TSST
toxic schock syndrome
lysins
hemolysins
hemolysins
lyse RBCs
pore formers
disrupt target cell membrane by causing formation of unregulated channels
how are channel pores formed?
- multimer of one bacterial protein that inserts into membrane
- complex of two or more bacterial proteins that inserts into membrane
- binding to target cell membrane protein leading to unregulated opening of pore
phospholipases
- cleave phosphatidylcholine (lecithin) or spingomyelin (all over cell so it will affect lots of cell types)
- due to the abundance of substrate, can affect virtually all cell types
- one or more forms expressed by a large number of bacterial species
- probably facilitate bacterial dissemination and allow bacteria access to nutrients normally found only in the host cell cytoplasm
cholera toxin, botox, tetox
high level of target cell specificity
phospholipases
promiscuous, low cell specificity
alpha toxin of C. perfringens
phoshpolipase
beta toxin of staph aureus
sphingomyleinase
superantigens
staphylococci
what grows if tampons are kept in too long
irritated the vaginal environment to that favoring staph aureus
what caused toxic shock syndrome
many strains of staph + strep
patients most commonly affected by toxic shock syndrome
- menstruating women
- post surgical, either gender if you allow staph aureus to get through a barrier during surgery/injury
clinical features of toxic shock syndrome
- high fever
- hypotension
- chills
- nausea, vomiting, diarrhea
- erythematous rash all over leads to desquamation especially on hands and feet
classic pyrogen
LPS
pyrogenic
causing fever
many strains of strep make SPEs
streptococcal pyrogenic exotoxins such as SpE A + C
TSST-1
damage due to superantigen activation of T cells, TSST-1 activates 20 to 25% of T cells
superantigens
interact with T cell receptors inappropriately
-they bind to a site on the TCR outside of the AG specific TCR binding site
superantigen binds to all TCRs with a
shared structure, and many TCRs share the same structure outside the Ag binding site
superantigens binds to class
Class II MHC molecules on APCs
cell surface interactions with T cells and APCs during TSST mimic
normal Ag presentation and stimulate large numbers of T cells
TSST
toxic shock syndrome toxin
Toxic shock syndrome toxin
- superantigen
- activates up to 1 in 5 T cells
- causes massive release of cytokines, TNFa, IL-1, IL-2, IL-6
- contrast to conventional antigen: approximately 1 in 10,000 T cells activated
- made by many staph, strep strains
toxic shock syndrome
desquamation of hands and feet
A-B toxins
activity + binding domain
mechanism of AB toxins active in cytoplasm
- protease
- nuclease
- ADP-robosyl transferase
- adenylate cyclase
A-B toxin entry
- binding
- receptor mediated endocytosis
- acidification release of a subunit across membrane
A-B toxin entry= diptheria
directly transits cell or it can undergo receptor mediated endocytosis
A/B toxins
A is active domain B is binding domain
what are exotoxins that act at a distance
A/B toxins- B domain may deliver toxin to host cell surface for damaging effects or may permit internalization of toxin such that it acts inside cells
“A” domains
proteases, nucleases, ADP-ribosyl transferases, adenylate cyclases
Are A/B toxins homologous?
NO, they contain a great variety of enzymatic activities that are delivered to host cells by a common strategy
type III secretion system -dependent intoxication
bacteria bind to host cell, then inject toxin into cytosol
legionella
use a lysosomal pathway + keep cells from undergoing apoptosis
type III, IV, V, + VI secretion systems deliver non A/B toxins directly into
cytosol of host cells
NON A/B toxins
similar to A/B toxins
- enzymes that work in the cytoplasm to subvert host cell phsyiology, protecting themselves from host immune response
- antibiotics are irrelevant to toxin if bacteria grow intracellularly
legionella pneumophila
> 150 effector molecules
that prevent endosome-lysozomal fusion and lead to the production of a unique compartment where legionella can grow intracellularly
-some effectors prevent programmed cell death
vibrio cholerae
gram neg rods
what organism causes cholera?
vibrio cholerae
what kind of environment is vibrio cholerae found?
aquatic environments
how do we acquire vibrio cholerae?
contaminated water or food like uncooked shellfish
where does the cholera toxin act in our body?
small intestine
Can cholera be self-limiting?
yes, if patient is kept hydrated
what leads to rice water diarrhea?
cholera
does cholera toxin kill its target cells?
no, it subverts their physiology such that ionic balance is lost and water move from cells into the lumen of the small intestine
How many liters of fluid can a patient lose per day?
5 gallons = 20kg= 44 lbs
What therapy is used to replace fluid that is lost
oral rehydration solution
Oral rehydration solution per liter
20g glucose, 4.2 g NaCl, 4.0 g NaHC03, and 1.8g KCL
If cholera patients are not too bad off
replace fluids orally
if cholera patient is very ill
get IVs of lactated ringer’s solution
Cholera’s mechanism of action
adenylate cyclase (regulator) is stuck in the “on” due to ADP-ribosylation of bound GTP, which prevents its conversion to GTP which turns it OFF
cholera toxin subunits
1A subunit + 5B subunits encoded by separate genes in the CTX phage genome
What keeps ADPR (ADP ribosylation of bound GTP) on?
cholera toxin + NAD with help from an activator
what occurs when GSAlpha (adenylate cyclase regulator) remains in the ON position
- continued activation of adenlyate cyclase
- dramatically increased cAMP
what happens in the intestine when GSalpha is ON and cAMP increases?
- decreased Na+ absorption by villus cells
- increased Cl- secretion by crypt cells
- DRAMATIC WATER LOSS THROUGH LUMEN OF GUT
what do cholera patients get when there is RAMATIC WATER LOSS THROUGH LUMEN OF GUT
rice water stool
does cholera kill cells?
NO!
cholera
- cholera toxin action in small intestine
- toxin A subunit is ADP-ribosyl transferase that alters a regulatory subunit of adenylate cyclase
- results in increased cAMP levels in cells–> decreased Na+ uptake and increased Cl- secretion–> massive water loss and “rice water” stool
- Na+ / glucose symporter is not affected, allowing oral rehydration with solutions containing salts + glucose
is cholera self liminting?
yes, if patient is kept hydrated
bacillus antracis
- AB toxin
- clear central spores
- gram + spore forming abcterium
what helped Koch develop the germ theory of disease and derive “Koch’s postulates?”
bacillus anthracis
What kind of infection is bacillus anthracis
zoonotic infection, derived from herbivores such as cattle and sheep
woolsorter’s disease
derived from catle and sheep; bacillus anthracis
domestic terrorism via US mail caused 22 cases of anthrax
11 inhalation + 11 cutaneous via envelopes
3 ways bacillus anthracis
skin, Gi Tract, Lungs
anthrax is a
multi component A +B toin
how anthrax gets in the skin
scrape or scratch- scores germinate-anthrax toxin produced-local lesions-tissue necrosis-pustules and ulceres
how anthrax is presented in the GI tract
ingested spores germinate– anthrax toxin produced-local lesions-possible dysentery
what is the most common way disease is presented by anthrax?
on the skin
how anthrax is presented in the lungs
inhaled spores germinate-septicemia-high mortality
B subunit of anthrax
“PA” for protective antigen, binds to type 1 membrane protein causing receptor mediated endocytosis
A subunit of anthrax
LF or EF
PA + LF anthrax
lethal activity
PA + EF anthrax
edema
EF+ LF anthrax
inactive
LF antrhax
letal factor, a Zn++ dependent protease that induces cytokine formation in macrophages + lymphocytes (A2 + B)
EF
edema factor , an adenylate cyclase enzyme that increases levels of cAMP
how does EF cause edema + phagocytic response
leads to the formation of ion= increase fluid release, permeable pores in membranes, causing edema and phagocytic response
tetanus + botulinum neurotoxins
synthesized as a single polypeptide chains
what synthesizes tetanus
clostridium tetani
how do tetanus and botulinum neurotoxins lead to disruption of neurotransmission
A subunits cleave proteins involved in docking of synaptic vesicles to plasma membranes
BoTox and Tetox
homologos + highly sequence similar toxins that affect neural transmission
Tetox is transmitted to cranial nerves by
intraspinal transmission among involved motor neurons (retrograde transport) OR by bloodstream delivery to neuromuscular junctions
TEtox is associated with
traumatic wounds/deep puncture (anaerobic)- dreaded “rusty nail”. leads to spastic paralysis (lockjaw)
vaccine DDT2
tetanus toxoid generated by formalin treatment of TeTox
Botox prevents
release of neurotransmitter and acts at peripheral cholinergic synapses leading to flaccid paralysis
what toxin is heat labile
C. botulinum
heat labile protein
one that can be changed or destroyed at high temperatures.
does the C. botulinum toxin grow in the body?
rarely, except in infant botulism where there is colonization of the large intestine
how is C. botulinum introduced?
through contaminated food, and the toxin is heat labile
does C. botulinum kill targets?
Toxin does NOT act by killing target cells nor does it produce sepsis/fever.
How do we treat C. botulinum disease?
antitoxin + supportive care
What two toxins can damage at extremely low doses?
Botox and Tetox
How much of botox could kill all the people on earh?
.6kg
botox (botulinum?) and tetox (tetanus?) attack
same targets but different neurons
-you can take A from botulinum and put on B of tetanums and you can retarget
how many kDa are Botox and Tetox proteins
~150lDa
Botox and Tetox
Zn++ proteases that cleave proteins in involved in docking of synaptic vesicles to the plasma membrane of neurons
What proteins are proteolytically clipped at the hairpin to produce a light chain and a heavy chain that are held by a disulfide bridge
botoxin + tetoxin
what two toxins block similar steps in neurotransmission but affect different target neurons due to their B domains?
botox + tetox
locked jaw
starts in jaw but then whole body gets rigid
how do you die from botulinum neurotoxin
flaccid paralysis- you die of suffocation because you can’t breathe
tetanus and botulinum neurotoxins A subunits
cleave proteins involved in docking of synaptic vesicles to plasma membrane, leading to disruption of neurotransmission; opposite effects on host due to selection of target neurons by B subunits
botulinum toxin
peripheral neurons, blocks release of stimulatory neurotransmitters, flaccid paralysis
tetanus toxins
retrograde transport to CNS, blocks release of inhibitory neurotransmitters, spastic paralysis
