Final Exam 1 Flashcards
Hyaluronidase
Enzyme produced by a pathogen after attaching to host epithelium. Pathogen invades deeper tissues.
Hyaluronic acid
A polysaccharide that maintains organization of cells in host tissues
coagulase
An enzyme produced by the pathogen that causes clots to form around the infection site to protect the pathogen from immune cells. Coagulates fibrin
Immune cells will see the clos as normal, leave the pathogen inside inside the clot alone and thus then the pathogen can grow and divide
Streptokinase
(staphylokinase) dissolves clots to allow the pathogen to move into deeper tissue layers and the blood stream.
So this is an enzyme that is produced by the pathogen
AB-type exotoxins
Two-component toxins
B-subunit binds host cells (cell receptors) and facilitates the transport and release of the A-subunit into the host cell
The A-subunit has toxic activity. Enzymatic interruption of transcription, translation, cell signalling, etc. Action part!
Lots of organisms produce AB toxins
Diphtheria
Respiratory disease
Corynebacterium diphtheriae colonizes throat and upper respiratory tract
A buildup of fibrin clots, dead cells, and an immune response result in typical swelling of the neck and pseudomembrane formation in the throat. - can occlude the airway and cause death
Fatal if untreated (suffocation) or if the toxin (Diphtheria toxin) spreads to the heart, liver etc
DTaP vaccine
What bacterium causes Diphtheria?
Corynebacterium diphtheriae
DTaP vaccine
Diphtheria, tetanus, and pertussis vaccine
Diphtheria toxin
DT is the best studied bacterial toxin.
The Tox gene is located on a lysogenic bacteriophage β
- An AB type toxin
DT ADP ribosylates (elongation factor 2) EF-2, which stops translation - leading to host cell death (inhibits protein synthesis) - (DT catalyzes the addition of ADP to EF-2 - EF-2 ADP then blocks the elongation step of translation because EF-2 is inactivated)
Botulism
A neuromuscular disease that results when Clostridium botulinum either colonizes the GI tract or the toxin is ingested
Toxin is absorbed in stomach/small intestine and enters the blood stream where it targets motor neurons at neuromuscular junctions
The toxin produce makes it so that muscles cannot be contracted - flaccid paralysis
Treatment via antibiotics and antitoxin, but once the toxin is bound to its target, there is no treatment.
Mechanical respirators for breathing, death
Botulism Toxin (BoNT)
BoNT is the most potent bacterial toxin known.
Bot genes are located on the chromosome, plasmids, and prophage
An AB-type neurotoxin
B-subunit binds a host cell membrane receptor on motor neurons and translocates the A-subunit into the host cell
The various BoNT A subunits are endoproteases that cleave various SNARE proteins
SNARE proteins are required for exocytosis of NT
Synaptic vesicles thus can’t merge with the cell membrane to release ACh into the synaptic cleft where they normally initiate muscle contraction because the cleaved SNARE proteins are not functional
Muscles don’t contract without ACh binding
Digestion affected first, then limb problems, then breathing.
Tetanus
A neuromuscular disease that results when Clostridium tetani colonize a deep tissue wound (anaerobic).
Toxin diffuses away from the wound site and enters the blood stream where it targets the inhibitory neurons of motor neurons
causes spastic paralysis (lock jaw) - host cannot relax contracted muscles)
Treatment via antibiotics and antitoxin, but once toxin is bound to target, there is no treatment (6 month last)
DTaP vaccine
Tetanus toxin (TeNT)
Shares homology with BoNT, but targets different receptors
Tet genes located on a plasmid
An AB neurotoxin.
B subunit binds to host cell membrane receptor on inhibitory neurons and translocates the A-subunit into the host cell
A TeNT A-subunit is a endoprotease that cleaves the SNARE protein: synaptobrevin-VAMP
cleaved SNARE protein means that synaptic vesicles containing glycine cannot merge with the cell membrane to release glycine. Glycine normally inhibits motor neurons so when glycine is no longer released, the motor neurons will always be releasing acetylcholine and muscles will be in a constantly contracted state.
Cholera
An intestinal disease caused by Vibrio cholerae colonizing the small intestine.
Exposure to food and/or water contaminated with human feces.
Toxin targets intestinal epithelial cells
Causes severe diarrhea associated with life-threatening dehydration (cholera cots)
treatment by rehydration therapy and antibiotics
Rice water stool - diarrhea contains globs of membranes, mucous, and other cellular debris
Cholera Toxin (CT)
Shares homology with enterotoxins of pathogenic E. coli and Shigella
ctx gene is on a prophage
CT toxin is a hexameric AB-type toxin (AB5)
The B subunit finds to a host cell membrane receptor on intestinal epithelial cells and translocates the A-subunit into the host cell.
The CT A-subunit ADP ribosylates the alpha subunit of Gs proteins. Leads to constitutive activation of Gs and AC which increases cellular cAMP – activates PKA pathways
RESULT: cells top absorbing Na+ and Cl-, and PUMP Cl- and HCO3- into the gut lumen – water then rushes out of cells
Cytolytic exotoxins
Cytotoxins
Secreted toxin proteins that lyse cells - main role is to destroy cells to make nutrients available for the pathogen
ex. hemolysins
They function by using phospholipases
Some form pores in our cell membranes, causing them to lyse
Grangrene
skin tissue disease that results when Clostridium perfringens colonizes wound sites
Exposure via contaminated soil
Has an a-toxin that is a cytotoxin/phospholipase that causes necrosis in the wound.
The bacterium metabolizes released sugars and proteins- Mixed acid fermentation
Can lead to amputation
Treatment via antibiotics and debridement
Staphylococcus aureus alpha-toxin
cell destruction by S. aureus skin infections mediated by this toxin (an alpha hemolysin)
Toxin is a pore-forming cytotoxin (electrolyte balance kills the cells)
Accumulation of dead cells in the area forms pus
Treatment via antibiotics and drainage
Superantigens
Excreted toxin proteins that induce a massive immune response - toxins bind to immune cells and activate them in a non-specific manner (activate 20%)
- Normal pathogens/toxins activate 0.0001-0.001%….
The massive immune response induces high fever, low blood pressure, organ disfunction/failure, system shock (severe multiorgan failure) and death
ex.
S. aureus
- Toxic shock syndrome (TSST-1)
- Staphylococcus enterotoxin (food poisoning)
Streptococcus pyogenes
- Exotoxin A (scarlet fever, rheumatic fever) strep throat
- septocemia can occur
Indiscrimately activates helper T cells - ie complex is formed without the specific match. So get massive amounts of cytokines released that result in a cytotoxic storm - toxic shock
Toxic Shock Syndrome
Causes by TSST-1 produced by Staphylococcus aureus that enters the blood stream
Endotoxins
-part of the pathogen cell structure
- More prevalent when the pathogen is in higher concentration (more toxin present)
The IS responds by releasing pyrogenic (fever) cytokines, as well as causing an increase in heart rate, diarrhea/vomiting, low blood pressure, and inflammation.
large quantities of endotoxin can result in blood clotting, organ disfunction/failure, endotoxic shock (septic shock) and death
- Lipopolysaccharide (LPS) in gram negative - LIPID A
- Lipteichoic acid (gram positve ) - endotoxins
Lipopolysaccharide
Makes up the outer half of the outer membrane in Gram Neg cells. Lipid A is the endotoxin
The polysaccharide portion makes the molecule soluble
Induces fever and general inflammation
Large doses can cause tachycardia, blood coagulation
immunology
is the study of the components and processes used to resist pathogens and fight disease
immunity
the ability of an organism to resist infection
The innate immune system
The automatic ability to recognize and destroy a pathogen (or its products)
Fast (hours)
Does not require previous exposure, no memory
Sometimes all that we need to fight an infection
Reduces exposure, adherence, colonization and invasion of pathogenic organisms.
ie barrier defenses are included as well.
Adaptive (specific immunity)
The second line of defense
The acquired ability to recognize and destroy a specific pathogen or its products
Following infection, effectors learn to target a particular pathogen to generate a coordinated response
Slower (days)
Generates immune memory
Blood to lymph
The fluid that leaves the blood vessels is called lymph. In capillary beds, lymph drains out of blood vessels, floods the tissues and then drains into lymphatic capillaries which then go to lymphatic vessels which then go to lymph nodes.
Lymph re-enters the blood stream around the neck area.
Lymph nodes
Sampling ground
Lymphocyte-filled tissues that sample the lymph for pathogens, toxins, activated immune cells
Spleen
Lymphocyte filled tissue that samples blood for pathogens, toxins, activated immune cells
SCREENS THE BLOOD
Mucosa-Associated Lymphoid Tissues (MALT)
Patches of lymphocyte-filled tissue that sample the mucosa for pathogens, toxins, activated immune cells
ie any mucous layer exposed to the environment (GI tract, lungs)
What are the primary lymphoid organs?
The Bone marrow and the thymus where lymphocytes develop
Hematopoiesis
Process by which hematopoietic stem cells, in the bone marrow, differentiate into more specific cell types
- Stem cells are activated by cytokines
Form erythrocytes, leukocytes (0.1% of cells formed)
HSCs differentiate into
- lymphoid precursor cells (cell and antibody-mediated immunity)
- myeloid precursor cells (phagocytosis and inflammation)
Myeloid precursors become
-Mast cells
-Basophils
-Eosinophils
-Neutrophils
-Monocytes (Macrophages, Dendritic cells)
Antigen presenting cells
Dendritic cells
Macrophages
B cells
Granulocytes
Neutrophils, Eosinophils, Basophils, Mast cells
Which cells are involved in phagocytosis?
Dendritic cells, macrophages, neutrophils, eosinophils
Which cells are involved in the inflammatory response?
basophils, mast cells
Cells in innate immunity?
all cells from the myeloid precursors plus natural killer cells
Cell-mediated immunity
natural killer cells and T cells
B lymphocytes
mature in the bone marrow an then await activation in the secondary lymphoid organs
- naive B cells are activated by exposure to foreign antigen
T lymphocytes
mature first in the bone marrow and then in the thymus and then await activation in the secondary lymphoid tissue
Naive t cells are activated by exposure to foreign antigen
Natural killer cells
Formed from lymphoid precursors. Part of the innate immunity that identifies and destroys virus-infected, pathogen infected, and cancerous cells
MAcrophages
A differentiated monocyte
- Associate with tissues/organs (lungs, skin, etc)
APC
Phagocytose foreign cells/molecules and present antigens on MHCll cell surface receptors
They generally stay in the tissue and continue to gobble up pathogen
Can be hyperactivated by
Dendritic cell
A differentiated monocyte
APC
-Associate with epithelial cells (skin, mucosa)
Phagocytose foreign cells/molecules and present antigens on MHCll cell surface receptors
- Then move to lymphoid tissues and activate T and B cells
Phagocytic granulocytes
Both neutrophils and eosinophils release antimicrobials (defensins, proteases, lipases), cytokines and chemokines
Both phagocytose foreign cells and molecules
neutrophils
- bacteria and viruses
- important for general infection clear-out
eosinophils
- specialize in attacking parasites (eukaryotic parasites)
inflammatory granulocytes
basophils (in the blood)
mast cells (in mucosal tissues/layers)
Both release histamine, cytokines, and chemokines
Histamine causes vasodilation, increases vascular permeability (increase leakiness), and induces fever
Increase in blood flow and increase number of WBCs getting to the site of infection - WBCs can then leak out of the vessels and migrate through the tissue
Cytokines are
signal peptides
50 have been identified
Some of things they do….
- promote hematopoiesis
- induce fever (increase body T so that pathogen is less likely to be able to grow)
- attract and activate other immune cells
- further increase vasodilation
Chemokines are
chemoattractant peptides
Neutrophils and lymphocytes that have been activated by cytokines will follow the chemokine concentration gradient to enter the damaged tissue
Diapedesis
When phagocytes leave vessels after following a chemokine gradient as the cytokines had loosened the tight junctions of capillary endothelial cells
aka extravasation, transmigration, and exudation
PAMPs
Microbe-associated molecular patterns
PAMPs - pathogen-associated
incl. LPS, teichoic acid, peptidoglycan, etc
- patterns NOT found on host cells
bind to pattern recognition receptors on phagocytes like neutrophils - this induces phagocytosis, cytokine production and release of antimicrobial peptides (alerts the system that something is up)
PRRs
Pattern recognition receptors found on phagocytes like neutrophils.
binding induces phagocytosis, cytokine production and release of antimicrobial peptides (alerts the system that something is up) from the phagocyte
ex. Toll-like recognition receptors (TLRs)
- widely expressed in mammalian innate immune cells
Are are complement proteins activated
They are acellular peptides activated when they bind:
- Antibodies coating a pathogen
- Pathogens directly
- Mast cells and basophils (inflammatory granulocytes)
They enhance inflammation, phagocytosis, and pathogen lysis
Complement cascade activated
Classic Activation Pathway - MAC Attack
C1 complex binds to antibodies coating a pathogen
C1 recruits and activates C2 and C4 - which then each split into A and B components
C2A and C4B complex recruits and activates C3 and C5.
C3B and C5B recruits C6, C7, C8, and multiple C9 proteins that form a membrane attack complex (MAC Attack) in the pathogen membrane - leads to cell lysis.
What leads to enhanced opsonization?
The fact that phagocyte have both C3B receptors and antibody receptors – this amplifies phagocytosis
100x
Which complement proteins act as chemoattractants?
C3a and C5a - even though they ‘go away’, they create a chemical gradient that helps to attact more phagocytes
C3a, C4a, C5a enhance vasodilation by promoting the release of histamine and cytokines from basophils and mast cells
Which complement proteins enhance vasodilation?
C3a, C4a, C5a enhance vasodilation by promoting the release of histamine and cytokines from basophils and mast cells
Interferons
special cytokines released from cells dying due to viral infection.
They migrate to surrounding cells and activate expression of antiviral genes - slows and limits the spread
sRNAs slow the progression of the viral infection
Humoral immunity is conferred by
B cells
- Antibody-mediated immunity
Cellular immunity is conferred by
T cells
cell-mediated immunity
Antigens
Molecules that interact with the immune system
- MORE specific than PAMPs
-incl. microbes, viruses, dander/pollen, toxins, and our own (self) molecules
Epitopes
are the specific parts of an antigen that interacts with the immune system
- The specific interaction/binding sites
- antigens can have multiple epitopes
- aka antigenic determinants
Immunogens
are antigens that illicit a response from the immune system
- under normal circumstaces, self-proteins and self-antigens are not immunogens.
In the ______, T cells are tested for their ability to react with:
thymus (selection occurs here)
- antigens (reactive to any, otherwise they are useless)
- self-antigen (they are destroyed if they do react with self-antigen
two stage selection process
only 5-10% survive
B cells form and mature in the _______ and tested for their ability to react with_________
B cells form and mature in the bone marrow and tested for their ability to react with self-antigen and they are destoyed if they do
The selection process is easier here - only have to go through one round of selection.
Examples of super antigens
S. aureus Toxic Shock Syndrome toxin
Staphylococcus enterotoxin
Streptococcus pyogenes - Exotoxin A
Which cells recognize antigens displayed on MHCII of antigen presenting cells?
Helper T cells - with T cell receptors
Interaction of the match is stabilized by CD4 – help to activate the T h cell
How are T h cells activated and what do they go on to do?
They are activated when an antigen presenting cell (dendritic) with the specific epitope presented on MHCII binds to the T(h) cell receptor and CD44 helps in this activation.
When activated, they undergo clonal expansion where they divide a lot to make copies and then they differentiate into
- Th1 cells - migrate to infection sites, release cytokines that activate macrophages (which were at the site gobbling)
- Th2 cells - which stay in the lymphoid tissue and release cytokines that activate B cells
- Memory T cells (these cells react to antigen regardless of whether it is presented on dendritic cell or not)
T helper 1 cells
Helper T cells differentiate into these when they are activated by binding an MHCII-epitope complex that fits with their specific T cell receptor
enter the circulation, migrate to infection sites and release cytokines that activate macrophages (which are hanging out and gobbling) presenting the specific epitope on MHCII
Improves phagocytosis
macrophages then release their own cytokines that induces other immune cells, fever, vasodilation, attract even more cells - positive feedback loop
T Helper 2 cell
Helper T cells differentiate into these when they are activated by binding an MHCII-epitope complex that fits with their specific T cell receptor
stay in the lymphoid tissue and release cytokines that activate B cells
B cells undergo clonal expansion into multiple copies of plasma cells and memory B cells
So the plasma B cells release antibodies specific to the antigen that was recognized by the T helper 2 cell
– PROVIDES ANTIGEN SPECIFIC ANTIBODY DEFENSE
A B cell receptor is an
antibody. Naive B cells have membrane bound antibodies called BCRs (1000’s) that only recognize one specific epitope
When an epitope matches and binds a BCR…
the antigen is phagocytosed - pathogen degraded and destroyed, B cell displays antigen on MHCII
What forms an antigen binding site?
One light chain and one heavy chain interacting
Immunoglobulin monomers are bivalent
2L 2H chains - 4 polypeptide = Ab
IgM
Immunoglobulin mu
monomeric IgM functions as a BCR
Ab secreted by B cells during INITIAL exposure
serum IgM forms a pentamer
IgG
Immunoglobulin gamma
Secreted by B cells during subsequent exposure
serum IgG is a monomer
IgA
Immunoglobulin alpha
serum IgA is a monomer
dimeric IgA is secreted at mucosal surfaces
- binds to mucin and is found in tears, sweat, colustrum, milk
Involved in preventing pathogens from reaching epithelium
IgD
Immunoglobulin delta
we dont know what monomeric IgD functions as. Maybe serves as a B cell receptor but we are not sure.
memory B cell activation?
IgE
Immunoglobulin epsilon
displayed on basophils and mast cells after being taken up by them
triggers release of histamine and proinflammatory cytokines when they come into contact with the antigen (specific)
In the secondary antibody response
Memory B cells rapidly differentiate into plasma cells
No need for activation of Th2 cells to activate B cells here
Class switching such that
IgG is produced in the blood
igA is produced at the mucosal surfaces
intracellular pathogen detection
intracellular pathogens may release foreign cellular antigen that are directed to proteosome and then are displayed on MHCI
MHCI
present on all nucleated cells. Presents both self and foreign antigen
T c cells have TCRs that recognize
T c = cytotoxic T cells
MHCI displaying a specific antigen
naive T cells interact with MHCI-epitope complexes (there are unique TCRs for every epitope)
Tc cell coreceptor CD8 stabilizes and helps to activate T c cells when interacting with the MHCI-epitope complex
B7 and C28 binding is also necessary for activation
T c cells have TCRs that recognize
T c = cytotoxic T cells
MHCI displaying a specific antigen
naive T cells interact with MHCI-epitope complexes (there are unique TCRs for every epitope)
Tc cell coreceptor CD8 stabilizes and helps to activate T c cells when interacting with the MHCI-epitope complex
B7 and C28 binding is also necessary for activatio
What happens when Tc cells are activated?
They release perforin that creates pores in the target membrane of infected cell
releases granzyme - goes into the pores and convinces the cell to undergo apoptosis
also releases cytokines which attract and activates other immune cells
They then also undergo clonal expansion to make multiple copies of themselves and also of memory Tc cells in case of subsequent infection
Natural killer cells are activated when
they detect stress proteins on cells that dont have MHCI
- they get suspicious when cells dont have MHCI - many infected/cancerous cells stop presenting MHCI
Upon activation, NK cells release perforin and granzyme (acts just like T c cell) - makes cells undergo apoptosis
MHCI inhibits NK cell activation
AI2
autoinducer 2, a universal autoinducer - involved in interspecific quorum sensing
furanosyyl borate diester
At quorum - upregulation of genes across multiple species via the activation of transcription factors.
Important in HGT and biofilm formation
can also be involved in bacterial warfare - negative side.
ie production of bacteriocins.
A. fischeri produces the autoinducer:
AI-1
The first one discovered!
acyl homoserine lactone.
What activates LuxR?
LuxR is a response regulator that is activated by the binding of AI-1 (when AI-1 is at high concentrations)
Activated LuxR binds to activator binding sites on the LuxICDABEG operon
Which are associated with B cells?
Antibody receptors
MHC II
MHC I
Which cells have pattern recognition receptors?
Phagocytes
Cytotoxic T (Tc) cells specifically attack
Cells infected with an intracellular pathogen
Things commonly secreted by T1SS
bacteriocins, biofilm mediators, RTX toxins,
Things commonly secreted by T3SS
a variety of cytotoxins
Things commonly secreted by T2SS
AB toxins such as ExoA and CT
Type 6 SS is commonly used in
microbial warfare
ATP-mediated T4-phage like injecction system
Things commonly secreted by T5SS
exonucleases (IgA protease), adhesins, cytotoxins
