exam1 Flashcards
Symbiosis
intimate association of 2 or more different species
living together of unlike organisms-Heinrich Anton de Bary
doesn’t imply benefit or detriment to either partner
mutualism
both partners benefit
commensalism
one benefits, other is unaffected
ammensalism
one benefits, other is harmd: parasitism, predation, pathogenesis
where do microbes live in our bodies
skin
mucosa
-urogenital tract
-resp tract
-gastrointestinal tract
>oral
>stomach
>gut-intestineswhere are microbes not found in our bodies
internal tissues
circulatory system
nervous system
holobiont view
organisms are comunities
hologenome: host+micro genome
dominant bacteria in humans
4 phyla dominate:
- Bacteroidetes- gram-negative
- proteobacteria- gram negative
- firmicutes- gram-positive
- actinobacteria- gram positive
fungi dominant in humans
maninly yeasts
archaea in human microbiome
gut, oral tract and vaginal tracts
skin: about 5% compared to Bacteria
fungus in humans
much less abundant than bacteria
located in: skin, oral tract, vaginal tract, gut, resp tract
role of normal microbiota in health?
-nutrition
digest food esp plant polysacchrides, produce short chain fatty acids, provide vitamins, impact systemic metabolites- bloodstream
-barrier
restrict growth of other microbes. colonization resistance-prevention of pathogen growth.
reinforce barrier functions of epithelia
–immune
Educate the immune system
-Community
alter the local ecosystem via metabolic activity
interact with other microbes
the old friends hypothesis
we evolved with a community of normal microbiota
-the holobiont is the functioning unit
disruption to the normal microbiota ma have deleterious effects on health
such as diet, hygiene, medical practices disturbing diversity
population growth is increasing exposure to novel pathogens
commensal pathogens
members of normal microbiota that may cause disease in some situations
immunity
resistance to disease, specifically infectious disease
immune response
coordinated reaction of the immune system to fight and keep in check infection and against transformed cells
self vs non-self
self are normally healthy host antigens
non-self are foreign or modified self antigens
memory
the ability of adaptive response to mount more rapid, larger, and more effective responses upon repeat encounters, basis behind vaccination
tolerance
unresponsiveness to self antigens, may be broken
3 levels of immunity
INNATE IMMUNITY
1) external defenses
- skin
- mucous membrane
- secretions
2) internal defences
- phagocytic cells
- antimicrobial proteins
- inflammatory response
- natural killer cells
AQUIRED IMMUNITY
3)humoral response (antibodies) and cell mediated response (cytotoxic lymphocytes)
Innate immunity
1) external defenses
- skin
- mucous membrane
- secretions
2) internal defences
- phagocytic cells
- antimicrobial proteins
- inflammatory response
- natural killer cells
aquired immunity
3) humoral response (antibodies) and cell mediated response (cytotoxic lymphocytes)
includes: helper cells, regulatory cells, cytotoxic cells, B lymphocytes, plasma cells, antibodies
frst line of defense- anatomical chemical/nevironmental/physical
barriers: block entry of pathogens-skin
chemical: inhibit growth ex lysozymes in tears
environmental factors: non-permissive conditions ex stomach acid, anaerobic areas
physical removal: urine flow, mucociliary escalator
biological- the normal microbiota
where do cells mature and get educated
the bone marrow or thymus
what is the site of immune cell initiation
lymph nodes
spleen
lymphatic vessels
hematopoiesis
immune cell generation and development
a programmed set of steps modulated by growth factors
signaling molecules control development
occurs throughout life span
types of progenitor cells
lymphoid cell lines
myeloid cell lines
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its “target” cell.
lymphoid cell lines
NK cell T cell B cell Dendritic cells bone marrow->hematopoietic stem cells-> common lymphoid progenitro
myeloid cell lines
Bone marrow-> Hematopoietic stem cells-> common granulocyte/macrophage progenitor: eosinophil macrophage basophil mast cell neutrophil dendritic cell (also in lymphoid line)
t lymphocytes activation/generation
are activated in the thymus
b lymphocytes activation/generation
are activated in the bone marrow
cytokines
small secreted proteins involved in communication
lymphokines- made by lymphocytes
interleukins-made by one leucocyte and communicate with another
chemokines-low molecular weight, involved in chemoattraction (any of a class of cytokines with functions that include attracting white blood cells to sites of infection.)
cells involved in innate immunity
phagocytes: neutrophils and monocytes which divide into macrophages and dendritic cells NK cells eosinophils basophils mast cells
-dendritic cells (bridge gap between innate and adaptive immunity)
mediators are the complement system and cytokines
mononuclear leukocytes are monocytes, macrophages and dendritic cells (myeloid DCs and Lymphoid DCs)
mononuclear leukocytes
mononuclear leukocytes are monocytes, macrophages and dendritic cells (myeloid DCs and Lymphoid DCs)
segs and bands
segas- segmented, are mature neutrophils
bands- are immunture
normal neutrophil levels in blood are about 5000, mostly sges
during infections these rise
and during sepsis (presence of toxins/bacteria) the bands are high and segs low because they don’t have time to mature
MAMPs and PAMPs
microbe associate molecular patterns
immune system cells produce pattern recognition receptors
MAMPs and PAMPs are produced by benign and pathogenic microbes
relatively non-specific except host doesn’t have them
ex: lipopolysaccharide, lipoteichoic acids, peptidoglycan fragments
PRR
pattern recognition receptors
many different kinds
-TLR are tolllike receptors that are in the surface of or inside cells
NLR are nod like receptors that are intracellular proteins
different cell tpes have diffeent PRR, allowing them to detect and respond to different microbes
recognition leads to phagocytosis
phagocytosis
neutrophils- segs- mature into having greater than a 3 lobed nucleus, when die form pus
monocytes- are in the blood-> differentiate into macrophages
macrophages- in tissue
all function to ingest and destroy microbes
steps: leukocytes are called to site by mediators-?adhesion-> traverse blood endothelial layer-> squeeze into extra-capillary space- dispedesis
migrate to site of bacterial infection
Superorganism
is a group of synergetically interacting organisms of the same species. a social unit of eusocial animals, where division of labour is highly specialised and where individuals are not able to survive by themselves for extended periods.
Metagenome
All the genetic material present in an environmental sample, consisting of the genomes of many individual organisms
Virome
collection of viruses in and on the human body
- What else makes up our microbiome? How have we learned about the human microbiome, what is the project name and what techniques are used?
Archaea, viruses, fungi (mainly yeasts), protists, animals (mites, worms)
Culturing, molecular analysis
Project: the human microbiome project phase 1 and NIH integrative human microbiome project
Learned things through longitudinal sampling- people in the same longitude has same micrbiota
- What is the Old Friends Hypothesis? How does it relate to the concept of dysbiosis?
we evolved with a community of normal microbiota
-the holobiont is the functioning unit
disruption to the normal microbiota ma have deleterious effects on health
such as diet, hygiene, medical practices disturbing diversity
population growth is increasing exposure to novel pathogens
Dysbiosis (also called dysbacteriosis) is a term for a microbial imbalance or maladaptation on or inside the body,[1][2] such as an impaired microbiota. For example, a part of the human microbiota, such as the skin flora, gut flora, or vaginal flora, can become deranged, with normally dominating species underrepresented and normally outcompeted or contained species increasing to fill the void. Dysbiosis is most commonly reported as a condition in the gastrointestinal tract,[2] particularly during small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO).[3][4] It has been reported to be associated with illnesses, such as periodontal disease, inflammatory bowel disease,[6][7][8] chronic fatigue syndrome,[9] obesity,[10][11] cancer,[12][13] bacterial vaginosis,[14] and colitis.[15]
MAMPS and Toll-like receptors:
MAMAPS and PAMPs are produced by benging and pathogenic microbes. They are nonspecific except that the host doesn’t have them. Toll-like receptors are PRRs that are on the surface of or inside cells
b. PRRs and NLRs:
Nod-like recptors are intracellular proteins
PRR: different cell types have different PRRs allowing them to detect and respond to different microbes- recognitions leads to phagocytosis. Immune system cells produce these
c. Antigen/epitope
foreign substance that induces an immune response. Made up of epitopes (smaller antigenic determinant). Antigens are recognized by receptors on B cells and T cells. B cells can recognize antigens without help, but T cell receptors only recognize antigens when they are presented via MHC (MHC1 on all nucleated cells except red blood cells, MHC2 only on immune antigen presenting cells- macrophages, dendritic cells, B cells)
d. Antigen-Presenting Cell
Dendritic cell, macrophages, B cells
e. Lymphocytes
B cells and T cells. Small white blood cell with a single nucleus. Function is to eliminate antigen
f. Chemotaxis
movement of an organism/cell in response to a stimulus.
g. Cytokines Lymphokines- Interleukins leucocyte Chemokines
small secreted proteins involved in communication
Lymphokines- made by lymphocytes
Interleukins- made by one leucocyte and communicate with another
Chemokines-low molecular weight, involved in chemoattraction
Antibodies/Immunoglobulins
are made of 4 peptides, 2 heaby 2 light. They have a variable region that determines antigen binding. They have a constant region that determines the class of antibody-biological activity. The constant regions bind phagocytes and activates processed involved in removal of the pathogen
i. Complement
activation-group of proteins that circulate in the blood, they eventually go through a cascade and the net effect is anti-microbial. Most are enzymes, different subunits have different functions. Form MAC- microbial attack complex- effective against Gram neg bacteria (gram pos have peptooglycan cell wall so are not affected)
There are 3 pathways to activate the complement: alternate, lectin (for fungi) and classical (with antibodies). Alternate and lectin are part of the innate immune respone. Classical pathways required adaptive response.
Steps:
1) lyse bacteria by forming a MAC.
2) Tag pathogens to enhance recognition and destruction by phagocytes (opsonization)
3) activate inflammatory response by triggering release of histamine from mast cells
4) enhance clearance of antigen-antibody complexes
j. Antibody-Mediated Immunity
: leads to the production of antibodies, critical in protection from extracellular pathogens and soluble toxins.
B cells play main role in this, although T-helper cells (CD4) are also needed
B cells are made in bone marrow, after stimulation B cells are activated and become plasma cells (antibody factories)
B cells also have immunoglobulins on their surface and are also antigen processing cells
Major functions:
-neutralize microbes and toxins, prevent binding (antibodies block binding of virus or exotoxin)
-opsonization (pathogen is marked for phagocytosis) and phagocytosis of microbes
-complement fixation with goals to lyse microbes, opsonize and phagocytize, and mediate inflammation
-facilitated aggulutination of bacterial cells- make a big glob of cells that can’t affect host as well.
k. Hematopoeisis
production of blood cells and platelets in the bone marrow
A hematopoietic stem cell is a stem cell that can differentiate into other cells
A programmed set of steps, modulated by growth factors. Signaling molecules control development. Occurs throughout lifespan
l. Cell Mediated Immunity:
T cells are the stars, T cells are made in the bone marrow but educated in the thymus, play a major role in combating intracellular pathogens, although important in AMI also
can only recognize antigens in context of MHC
different types of t cells: T helper CD4+ and T cytotoxic CDB+
CMI’s role in immunity is the death of the pathogen.
m. Diapedesis
cells squeezing into extra-capillary space (during phagocytosis/inflammation esp)
n. MHC-which cells express each:
MHC1
MHC2
i. MHC 1 : present on all nucleated cells (except RBCs)
ii. MHCII: only present on immune antigen presenting cells- macrophages, dendritic cells, B cells.
o. Histamine
released during inflammation from damaged cells. Is a chemical mediator. . Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.
q. Tolerance
immune cells are not able to react with self antigens. Self reactive cells are destroyed during development of the immune response. Can be good or bad
r. Opsonization
process by which the pathogen is marked for ingestion and elimination by the phagocyte. The microbial pathogen associated molecular patterns (PAMPS) bind with the endocytic pattern recognition receptors (PRRs) pf phagocytes which mediates neutrophil mediation or macrophage phagocytosis
s. Memory
the immune response to a specific antigen is faster and stronger upon subsequent exposure because the initial antigen exposure induced growth and division of antigen-reactive cells, resulting in multiple copies of antigen-reactive cells.
Therefore, second responses are quicker and more vigorous due to memory
t. Phagocytosis
neutrophils (segs- so mature with more than 3 lobed nucleus) are involved. Monocytes are in the blood, and mature into macrophages. All finction to ingest and destroy microbes.
Steps in phagocytosis: leukocytes are called to site by mediators, adhesion occurs, traverse (travel across) blood endothelial layer, squeeze into extra-capillary space (called diapedesis), and then they migrate to the site of bacterial infection.
Cell eating:
1) bacteria become attached.
2) bacteria are ingested,
3) phagosomes fuse with lysosome- forming phagolysosome..
4) bacteria killed
Bacteria are killed by phagocyte in 2 possible ways: oxidative burst or chemicals/enzymes directly
Oxidative burst: O2 dependent. Crank up specific enzymes to make H2O2, NOx- highly reactive oxygen byproducts that go and oxidize bacterial proteins which damages them
Chemicals/enzymes: used to attack and destroy them
NETS: neutrophils also trap microbes- extra cellular killing. Produced by activated macrophages, extrude DNA. It is a sticky network, and it kills and traps extracellular microbes
NET
NETS: neutrophils also trap microbes- extra cellular killing. Produced by activated macrophages, extrude DNA. It is a sticky network, and it kills and traps extracellular microbes
- What are the basic levels of host response to an infectious agent. What is the relative specificity of each?
1st line of defense: physical and chemical barriers->immediate response->totally nonspecific ex: skin, mucous membranes, chemical
2nd line of defense: innate immunity->several hours-several days->non-specific, but recognition of microbial associate molecular patterns (MAMPS)
3rd line of defense: adaptive immune system-> about 96 hours with stronger secondary response->highly specific, antigen receptors-> antibody mediated, or humoral immunity, B cells and T cells
a. What are some examples of 1st level defenses?
Examples: chemical/environmental/physical
Barriers: block entry of pathogens-skin
Biological: normal microbiota
Chemical: inhibit growth-lysozymes in tears
Environmental: non-permissive conditions such as stomach acid, anaerobic areas
Physical: removal such as urine flow, mucociliary escalator
dendritic cells:
bridge innate and adaptive response, antigen presenting cells
Like macrophages and neutrophils, dendritic cells (DCs) are considered professional phagocytes.
NK
part of the innate response although derived from lymphoid cell progenitor. NK cells have a limited set of invariant receptors. Are activated by indicators of infection, cancer or other types of damage
Activation: they detect non-healthy cells. Healthy cells express inhibitory signals that let cells know to leave them alone, but unhealthy cells are missing this signal. Once activated, NK cells produce cytotoxic granulaes that kill abnormal cells and IFN-y which helps phagocytes kill better
Monocytes
involved in the innate response- mononuclear leukocytes- are present in the blood- function is to ingest and destroy microbes
differentiate into macrophages
Macrophages
involved in the innate response- mononuclear leukocytes, present in tissue. Monocytes differentiate into macrophages. Function is to ingest and destroy microbes. Antigen-presenting cell
Neutrophils
segs- segmented/mature neutrophils.
Bands-immature neutrophils.
Normal levels of neutrophils in blood are mostly segs- about 5000, they rise during infection.
During sepsis (presence in tissue of harmful bacteria and toxins) segs are low, bands are high since they don’t have time to mature. Function is to ingest and destroy microbes.
Also trap microbes by extracellular killing called NETS- produced by activated macrophages. They extrude fibers made of DNA and produce a sticky network and trap and kill extracellular microbes.
B cells:
involved in adaptive response, involved in both innate and adaptive response. Are antigen presenting cells.
Are made in the bone marrow, after stimulation, B cells are activated in spleen/lymph nodes and become/differentiate into plasma cells to make antibodies
very imp in antibody-mediated immunity,
B cells also have immunoglobulins on their surface and are also antigen processing cells.
Some B cells differentiate into memory cells and are primed and ready for a rapid response.
B cells are needed for extracellular pathogens
plasma cells:
B cells differentiate into these. Make antitoxin antibodies
T cells (different markers and types-particularly Th1 and Th2):
T cells are made in the bone marrow but educated in the thymus,
involved in adaptive response, become helper cells and help other cells carry out their functions, and cytotoxic cells CTL and kill infected cells.
T cells need MHC1 and MHC2 to recognize antigens. can only recognize antigens in context of MHC
T cell signaling requires 2 singals: 1 from the antigen, and 1 from MHC-> this leads to a series of events such as proliferation, differentiation into an effector.
The T cell produces cytokines providing another signal.
T cells are the stars in cell-mediated immunity,
play a major role in combating intracellular pathogens, although important in AMI also
different types of t cells: T helper CD4+ and T cytotoxic CDB+
T cell activation: most T cells become activated in lymph nodes-> may become Th (helper) or Tc (cytotoxic) cells.
T helper cells: help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells.
t cytotoxic cells: kill infected/compromised cells
Therefore t cells have 2 major receptors TCR and CD4 or CD8
T helper cells
T helper cells: CD4 help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells.
CD4: need MHC2- subtypes Th1 and Th2. Different signals induce differentiation into different sub-sets
-Th2: T helper cells are activated by B cell-processed antigen, in concert with Class 2 MHC., needed for a response against parasitse
-Th1: needed for response against intracellular bacteria
T cytotoxic cells
kill infected/compromised cells
CD8: need MHC1 cells, needed for action against virus-infected cells.
- What are the roles of bone marrow, thymus, lymph nodes, other secondary lymphoid organs and peripheral lymphoid organs?
Primary role: where immune cells are generated, mature and are educated Bone marrow Thymus Secondary: Site of initiation Lymph nodes Spleen Lymphatic vessels Peripheral lymphoid tissue Mucosal associated lymphoid tissue ex: peyer’s patch (Peyer's patches are small masses of lymphatic tissue found throughout the ileum region of the small intestine. Also known as aggregated lymphoid nodules, they form an important part of the immune system by monitoring intestinal bacteria populations and preventing the growth of pathogenic bacteria in the intestines)
- What are the main phagocytic cells, where do they reside, what are the basic steps once a phagocyte encounters a MAMP and how do they kill microbes?
All function to ingest and destroy microbes
Neutrophils- in the blood, predominant white blood cells
Monocytes- in the blood
Macrophages-in tissue (monocytes differentiate into macrophages resident in tissue)
Steps in phagocytosis:
1) Leukocytes are called to site be mediators
2) Firm adhesion occurs
3) Cells traverse blood endothelial layer
4) Diapedesis- squeeze into extra-capillary space
5) Migrate to site of bacterial infection
Actual phagocytosis:
1) Bacteria become attached- microbes bind to phagocyte receptors
2) Phagocyte membrane zips up around the microbe- bacteria is ingested,
3) Phagosome fuses with lysosome and phagolysosome forms
4) Bacteria is killed by ROS, NO and lysosomal enzymes in phagolysozome
- Why is it called the Complement Cascade, what are the components (not specifics-but what are they) what are its 3 functions?
It is a cascade of 9 proteins with many subunits (total 30 proteins), most are enzymes, and the subunits have different functions
Final product is the Microbial Attack Complex (MAC) which is effective against gam neg bacteria
There are 3 pathways to activate the complement: Alternate, Lectin and Classical
3 functions:
1) Lyse bacteria by forming MAC
2) Tag pathogens to enhance recognition and destruction by phagocytes (opsonization)
3) Activate inflammatory response by triggering release of histamine from mast cells
4) Enhance clearance of antigen-antibody complexes
- What are the main steps in inflammation, what are the signs/symptoms?
Summary of inflammation: 1) tissue damage, physical insult, microbes enter-> 2)chemical mediators released from damaged cells –histamine- critical-> 3)increased permeability allows neutrophils to enter sites (diapedesis)-> chemitaxis of more cells -> 5) phagocytes engulf bacteria.
8. Symptoms: can be local or systemic, acute or chronic, required to rid or at least wall off injured areas. Signs are redness, swelling, heat and pain
- What do NK cells recognize and why/how do they NOT kill healthy cells?
NK cells are part of the innate response, though derived from lymphoid cell
NK cells are activated by indicators of infection, cancer or other types of damage
They detect non-healthy cellshealthy cells express inhibitory signals that let cells know to leave them alone but unhealthy cells don’t have this signalonce activated they produce cytotoxic granules that kill abnormal cells and IFN-y which helps phagocytes kill better
a. Clonal Expansion vs. Clonal Deletion
i. Clonal expansion: Clonal expansion of lymphocytes is a hallmark of vertebrate adaptive immunity. A small number of precursor cells that recognize a specific antigen proliferate into expanded clones, differentiate and acquire various effector and memory phenotypes, which promote effective immune responses.
ii. Clonal Deletion: Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes.[1][2] This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self.
b. Active vs. Passive Immunity
Active: host makes own immune response (antibodies)
Passive: host receives premade antibodies or immune cells
c. Natural vs. Artificial Immunity
Natural: host gets infected through “natural” exposure or through placenta or in colostrum
Artificial: prophylactic (intended to prevent disease) or therapeutic ex: vaccination, treatment after exposure.
- What is the basic structure of an antibody molecule, where does the antigen bind, and what is the role of the constant (Fc) portion?
antibodies are made of 4 peptides, 2 heavy and 2 light. They have a variable region that determines antigen binding.
The Fc region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system.
IgM
may be attached to the surface of a B cell or secreted into the blood, responsible for early stages of immunity
IgG
secreted by plasma cells in the blood, able to cross the placenta into the fetus
iii. IgA
found in mucous, saliva, tears and breast milk, protects against pathogens
IgE
: protects against parasitic worms, responsible for allergic reactions
- What are B cell and T cell receptors and what do they recognize? What is different about what they each can bind/see, or the form of the antigen which they can recognize?
T-helper cells CD4 need MHC2
T-cytotoxic cells CD8 need MHC1
T cell signaling required 2 signals- 1 from the antigen, 1 from MHC, T cells NEED MHC to present them with an an antigen
B cell receptors recognize native antigens or soluble
- How do we have the ability to respond to any antigen we may encounter?
- somatic recombination: animals have the ability to respond to 10^9 different antigens, but we don’t have that much DNA in our germ-line. But DNA is segmented and there is extensive rearrangement that can lead to tremendous diversity and allow us to respond to so many different antigens.
- Clonal expansion
- How do antibodies protect us from bacterial and all extracellular pathogen diseases? (4 roles)
1) They neutralize microbes and toxins, preventing binding
2) They cause opsonization and phagocytosis of microbes
3) They cause complement fixation with goals to lyse microbes, opsonize and phagocytize, and mediate inflammation
4) They cause facilitated agglutination of bacterial cells- make a big glob of cells that can’t affect the host (as well).
- How does our immune system protect us from viral and all intracellular infections?
Through cell mediated immunity- T cells are the stars
A: Phagocyte with ingested microbes in vesicles
-CD4 effector (helper) cells secrete cytokines->Macrophage is activated-> causes killing of ingested microbes
-cytokines secreted by CD4+ cells ->inflammation, killing of microbes
B: infected cell with microbes in cytoplasm
-killing of infected cells by CD8+ cells
- What is the difference between the primary and secondary immune response?
Primary responses are slow and weak- mostly IgM
Secondary responses are rapid and strong- involve mostly IgG
This is the basis for vaccination
(part of the antibody mediated immunity)
- What are the different types of T cells, including their CDs and their functions?
T cells divide into: CD8 and CD4 cells
CD8 are killer cells- need MHC1- kill virus-infected cells
CD4 divide further into TH1 and TH2 cells- both are involved in Cell mediated immunity, kill ingested microbe
TH1activate macrophages- needed for response against intracellular pathogens
TH2activate B-cells (which deal with extracellular pathogens), and are activated by B cells
a. What are the main subsets of CD4+ cells:
i. TH1: respond to intracellular bacteria, activate macrophages
ii. TH2: respond to parasites (extracellular), activate B cells
iii. TH17: respond to bacteria, fungi, inflammation
iv. Treg: are anti-inflammatory
IL-1
cytokine, interleukin-1, activates inflammation, fever. Source: macrophages, dendritic cells
TNF
cytokine, tumor-necrosis factor. Activates inflammation, fever, muscles catabolism, apoptosis. Sources: macrophages, T cells, mast cells
Interferon
cytokine tivates macrophages-makes them angry. Sources: NK cells, T-cells
IL-2
cytokine T cell proliferation, B cell proliferation, NK activation
20.A few examples of how microbes evade adaptive responses:
living intracellularly- avoids AMI
- capsules-hide surface antigens
- antigentic variation- changing and rearranging surface antigens
- overstimulating T cells- super antigens can lead to toxic shock
- decreasing expression of host MHC-CMV
- killing immune cells (ex HIV) and also digesting immunoglobulin
Autoimmunity
normally lymphocytes that recognize self-antigens are purged ut in some individs at certain times system self-tolerance fails and B and T cells against cell antigens are activated. Leads to tissue injury. Has genetic or infectious components
Pathogen
primary
opportunistic
commensal
Pathogen: a microorganism capable of causing disease- host and environmental factors are also important
Disease is when damage occurs
Most pathogens don’t cause diseases in all indivis infected- the carrier state/asymptomatic infections are an imp part of the disease cycle for many pathogens
Primary: has the ability to cause disease in healthy individs
Opportunistic: generally can’t cause disease in healthy individs, but can in unhealthy individs
Commensal: live in host where the host doesn’t benefit nor is harmed by the pathogen
Colonization and infection:
microbial growth at site
Carrier and chronic carrier
carrier is an individual with an asymptomatic infections- they maintain and transmit pathogen. Chronic carrier maintains and transmits pathogens for long periods- incubating and convalescent hosts ex: smallpox, polio etc
Attenuation and attenuated pathogen
: a pathogen that has lost its ability to cause disease
Virulence
a quantitative measure of the severity of the disease
virulence factor
any microbial feature that contributes to virulence
reservoir
sites at which infectious agents remain viable and from which infection can occur
Zoonosis
non-human animals that are reservoirs for pathogens. It can be an active pathogen for that animal or be carried commensally. Transmitted to humans by: direct contact, contact with animal products- meat, milk, fur, droppings, or transmission by vector
Vector
: living organism that is an intermediary (to transmit disease/pathogen)
Nosocomial
disease originiating in a hospital
Fomite
inanimate object that can transmit disease- involves pathogen being able to survive extended periods of time outside host and be tolerant of desiccation and starvation
Tissue tropism
is the cells and tissues of a host that support growth of a particular virus or bacterium. Some bacteria and viruses have a broad tissue tropism and can infect many types of cells and tissues. Other viruses may infect primarily a single tissue.
Endotoxin
: a toxin that is present inside a bacterial cell and is released when the cell disintegrates
Exotoxin
secreted by the pathogen
AB toxin
has AB structure- A is the active site, B is the binding site/part
Hemolysin
: lyses red blood cells
Leukocidin
affects white blood cells
pore forming toxin from bacteria
- Explain the basic steps in Koch’s postulates.
1) the microbe is found in all cases of disease, but absent from healthy individuals (critique- opportunistic pathogens/commensal pathogens)
2) the microbe is isolated from diseased host and grown in pure culture (critique- some microbes can’t be grown in pure culture ex: syphylus, sometimes microbes need other microbes to grow-polymicrobial
3) when the microbes is introduced into a healthy susceptible host, the same disease occurs
4) the same strain of microbe is obtained from the newly diseased host
3.What is the LD50 and ID50? How else can we measure virulence?
LD50 and ID50 are ways to measure virulence
LD50: the lethal dose- the number of microbes it takes to cause death in 50% of the population
ID50: infectious dose- the number of microbes it takes to cause notable disease symptoms in 50% of test animals/population (not death)
Other ways: human volunteers, animal models, cell tissue and organ culture models
What are the main types of reservoirs for pathogens? What is a zoonosis and nosocomial infection?
Reservoir- the site at which infectious agents remain viable and from which infection can occur
Types:
1) the environment- soil, plants, and water- pathogens can survive in a free-living state. Infection of a living host is not required. Generally not host-to-host transmission, but there are exceptions
2) non-human animals- zoonosis- can be transmitted to humans by direct contact, contact with animal products- meat, milk, fur, droppings, or transmission by vector
3) humans- can also be reservoirs- usually don’t produce symptoms in all infected individuals
-can be carriers who maintain and transmit pathogens
-can be chronic carriers- maintain and transmit pathogen for long periods
-can be incubating or convalescent (person recovering from disease)
4) the hospital- a unique envrionmen: susceptible people, movement of healthcare personall between patients, invasive procedures, antibiotics
Often a different set of pathogens and diseases than in community
Now: called healthcare associated infections (HAI)
- What are the main means of transmission for pathogens?
-Direct: from person to person through: secretions, direct skin contact, intimate person-person contact (STDs)
-Indirect via vector: living organism that is intermediary
Mechanical vector: moves pathogen
Biological vector: pathogen lives in vector, sometimes an essential part of microbial life cycle ex: lice, fleas etc
-Indirect via fomites: fomites are inanimate objects that can transmit disease ex: bedding, utensils- pathogen must be able to survive extended periods outside of host, be tolerant of desiccation and starvation.
-indirect via food- food may contain pathogen naturally, introduced during processing or prep
1) food intoxication- microbes grow in food, not in bodymicrobes produce toxin in foodperson ingests food with toxin
2) foodborne infection-microbes are present in foodperson ingests food with microbesmicrobes grow in body
- indirect via water: water harbors pathogen- natural inhabitants, some introduced into water by infected individual, next person consumes (fecal –oral route)
Water purification/waste treatment are critical. Can be domestic water or recreational water- lakes, rivers, ponds, water parks etc
- What is a mechanical vector versus a biological vector?
Mechanical vector: moves pathogen
Biological vector: pathogen lives in vector, sometimes an essential part of
- What is the difference between food-borne infection and food intoxication?
Food-borne infection: microbes are present in food, person ingests food with microbes and the microbes grow in the body
Food intoxication: microbes grow in food, not in body, microbes produces toxin in food, person ingests food with toxin
What are three things pathogens usually do to grow and colonize in a host? Must all be invasive?
Entry: portal of entry needs to be correct
Adhesion: human body has many ways of removing microbes at cells surfaces and attachment can prevent removal. Attachment may be needed for cell or tissue invasion
colonization and growth: pathogen needs to find a favorable niche and must be able to acquire nutrients, and must have appropriate environmental conditions
all ae not invasive- some pathogens stay at site of infection and are noninvasive, may produce local infection or release soluble mediators that have systemic effects
What kinds of molecules are adhesins and host receptors and what is the importance of this interaction?
The human body has many ways to remove microbes at cell surfaces, so attachment can prevent removal, and may be needed for cell or tissue invasion
Differnet proteins can be adhesins, and they have their own host receptors
What is significant about iron metabolism in animals? What are the main restrictions for iron access and how do pathogens overcome these restrictions? What are three examples of how pathogens can acquire iron from the host?
Free iron is very rare in the human body, humans control iron very strictly
Some microbes use siderophore to bind iron and use it doe themselves- can even compete with humans to absorbs it.
1) Microbes bind lactoferrin, transferrin or other hemopproteins at their surface and extract iron from these proteins
2) Produce hemophores-secreted proteins that bind heme
3) Produce proteases that degrade iron binding proteins, release iron
4) Acquire iron from hemoblobin or heme- take heme up into the cell and strip iron
- What types of cells do intracellular pathogens live in and how does entry into these cells differ?
Some enter phagocytic cells, other non-phagocytic cells, or both. Through trigger and zipper mechanisms
What are the zipper and the trigger mechanisms of cell entry? When and why are these
mechanisms needed?
Pathogens can enter phagocytic cells by actively promoting uptake, non-phagocytic cells but need their own uptake machinery, and some do both.
Zipper mechanism: pathogen has invasion proteins on its surfacecauses host cell to envelop it
Trigger mechanism: pathogen secrete something into cellinduces ruffling on the cell surfacecell ultimately absorbs pathogen
What are possible cellular locations for replication of intracellular pathogens?
Phagosome, phagolysosome, cytoplasm
Vacuoles: microbes activel remodel vacuoles, also need to redirect vesicular traffic to deliver nutrients
What are some host cell defense systems that intracellular bacteria may face? What
extracellular host defense systems are they escaping?
Intracellular: autophagy- formation of a double membrane around cytoplasmic contents, then delivery to lysosome. Used for recycling contents and for killing pathogens
Intracellular detection of PAMPS sets off host response: inflammation and pyroptosis (highly inflammatory form of programmed cell death)
Phagocytes, complement, adaptive immune response (avoid by interfering with MHC system, killing antigen presenting cells or T cells), antibodies (avoid by degrading them, binding them differently, varying their own antigens)
Extracellular: NET, phagosomes
.What are some possible mechanisms of host cell exit for intracellular pathogens? How do these differ in their outcome regarding the host immune system?
Some microbes escape to cytoplasm, produce pore-forming toxins that lyse phagosome. They sense phagosome developmental cues
Often require growth factors
What are some examples of the mechanisms by which pathogens can avoid the host immune response? Be able to describe a few specific examples.
they avoid or hide from the immune system-good defence
Living intreacellularly
Invading privileged areas not monitored by the immune syste,
Avoid/inhibit phagocytosis
Latency
- they actively derail the immune system= good offense
o kill immune cells
o interfere with immune signaling
o interfere with immune effector function (complement, antibodies or phagocytosis)
- avoiding innate response:
o evade phagocytosis: affect PRR detection/signaling
o kill phagocytes/prevent their activation/inhibit chemotaxis
o hide inside cells
o camoflauge as host
o avoid NETs
- survive inside phagocyte (prevent phagolysosome formation, neutralize it, escape to cytoplasm)
- avoid complement: prevent cascade, proteins that degrade the complement, prevent complement binding to cell
- avoid adaptive response
o interfere with MHC system, kill antigen presenting cells/T cells
o antibodies: degrade them, bind them differently, vary antigens
What are two mechanisms of cytolytic toxins
Cytolytic toxins lyse cells. Their 2 main modes of action:
Form pores
Degrade cellular membranes
Ex: hemolysins produce a zone of clearing on plates with Red blood cells
What are the modes of action and effects of diphtheria toxin, botulinum toxin and tetanus toxin?
Diphtheria toxin: an AB toxin, binds to specific receptor which is widely present on human cell types. “A” part of protein modifies EF-2 which is essential for protein synthesis. A single toxin protein can be lethal to cell
Botulinum toxin and tetanus toxin: neuroligocal toxins, inhibitory neuron releases glycine and GABA. Muscles go between contracted and relaxed states
Botulinum toxin causes an inability to contract muscles= flaccid muscles
Tetanus toxin causes an inability to relax muscles. it blocks release of acetylcholine from excitatory neruons which is needed for nerves to stimulate muscle resulting in flaccid state.
How do superantigen toxins act?
They are very resistant to heat, generally resistant to proteolysis (breakdown of proteins and peptides into amino acids by enzymes) and are highly resistant to dessication
superantigens (SAgs) are microbial products that have the ability to promote massive activation of immune cells, leading to the release of inflammatory mediators that can ultimately result in hypotension, shock, organ failure and death.
What is endotoxin? Do all bacteria produce it? How is it released? What is the main cause of pathology (disease symptoms) during exposure to endotoxin?
Endotoxin is LPS- lipopolysaccharide which is part of the outer membrane of gram neg bacteria. It is heat stable, released upon disruption of cell envelop. In the bloodstream, LBS-LPS binding protein- interact with CD14 and TLR4 on immune cells, induces secretion of proinflammatory cytokines, induces fever and local inflammatory response. Can also cause systemic inflammatory response syndrome (sepsis shock)
Mechanism: 1) macrophage ingests a gram-neg bacterium2)bacterium is degraded in a vauole, releasing endotoxins that induce the macrophage to produce cytokines3)the cytokines are released into the bloodstream by macrophages, through which they travel to the hypothalamus of the brain4) the cytokines induce the hypothalamus to produce a fever
- How do effector proteins differ from traditional microbial exotoxins?
- Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, using a type 3, a type 4, or a Type VI secretion system. bacteria inject effectors into their host’s cells, which then help the pathogen to invade host tissue- injected through membrane ruffling- cause cell death, suppress its immune system. Effector proteins are usually critical for virulence.
- Traditional/degradative enzumes attach host ECM or host cell materials. They facilitate invastion and nutrient access
acute infection
rapid onset, brief period of symptoms, resolution within days
acute with complications infection
like acute with rapid onset, brief period of symptoms and then resolution, but the illness slowly comes back -rare
latent infection
pathogen lies dormant and then symptoms appear and are resolved
chronic damage early infection
onset and then immune system responds early yet symptoms persist for a long time
chronic damage late infection
rapid onset and then the immune system doesn’t respond for a long time.
slow infection
after an extended period of latency, follows a slow, progressive course spanning months to tears
