Defense Flashcards
(44 cards)
1
Q
intrinsic vs extrinsic mortality
A
- intrinsic and extrinsic are separated to understand and measure the factors underpinning mortality
- intrinsic mortality: result of senescence and increase of age
- extrinsic mortality: result of environmental hazards and is constant with age
2
Q
mortality
A
- general causes of mortality are biotic (relating to living organisms)
1. competition for nutrients
2. predation
3. infection
4. injury - all contribute to evolution, b/c successful lineages have evolved mechanisms that best cope with these risks
3
Q
Coevolution
A
- organisms live/evolve in same environment as one another so they affect each other
- organisms evolve mechanisms of adaptation and counter adaptation (arms race)
- coevolution = important driver of evolution
- ex: bacteria and immune system always evolving
- microorganisms can evolve rapidly, and host needs to adjust accordingly to survive
- development of eukaryotes allowed organisms to develop specialized organelles (endosymbiotic theory)
- it’s speculated that the development of sexes is also a consequence of this requirement for a continuous adaptation
4
Q
Host Defenses
A
- humans evolved a series of barriers and mechanisms that allow peaceful coexistence with some commensals and defensive strategies to prevent death
- exposure to commensals in early life promotes development of a healthy/functional immune system
- lack of exposure to commensals can lead to autoimmune diseases
5
Q
Innate vs Adaptive defensives
A
Innate
- immediate, rapid response
- physical barriers or inflammation
- generalized response, nonspecific
adaptive
- slower response – few days
- specialized response
- requires recognition of pathogen
- repeated exposure to molecules will cause increased responses (trained to respond to invaders)
6
Q
Innate immunity: Physical Barriers
A
skin: forms a protective outer layer that most viruses and bacteria can’t penetrate
hairs & cilia: sweep particles outwards until they can be expelled
mucous membranes: secrete mucus which traps particles
gastric juices: kills most of bacteria you swallow
saliva & tears: contain enzymes that prevent bacteria from multiplying
7
Q
innate immunity: Phagocytic cells (APC)
A
phagocytosis:
1. phagocytic cells recognize specific epitopes on surface of bacteria (LPS) or cells that need to undergo turnover
- some particles can’t be recognized by the phagocyte unless opsonized (tagged with antibodies/opsonin’s)
2 they engulf (eat) bacteria, harmful particles, and dead cells
3. the particle is ingested on the form of a phagosome that is then fused with lysosomes containing digestive substances (H2O2, HOCl, O2-) and degrade them
- some cells “present” antigens to other cells of immune system: monocytes, macrophages, neutrophils
-macrophages:
- are important because they are first line barrier and set up adaptive immunity- secrete cytokines which regulate the immune response
8
Q
Innate Immunity: Inflammation
A
- macrophages secrete cytokines to stimulate inflammation, eliminate the original cause of injury, and promote repair
- 4/5 Cardinal Signs
1. Redness because of vasodilation & increased blood flow
2. Swelling because of vasodilation
3. Heat because increased blood flow and blood is warm
4. Pain because of fluid build up and nociceptors
5. Loss of function (sometimes not counted) - Problem in current day is the constant low grade systemic inflammation in humans that causes diabetes and heart disease
9
Q
Adaptive Immunity
A
- Innate immunity stimulates and overlaps with acquired/adaptive immunity
- Cytokines released by inflammatory response attract lymphocytes to site of immune reaction
- Acquired immunity is directed at a specific pathogen and takes longer to develop
10
Q
Adaptive immunity: Lymphocytes
A
- Each lymphocyte interacts with a specific antigen(pathogen)
- Millions of lymphocytes can recognize millions of antigens
- Keep only a few memory lymphocytes for a specific antigen at all times
- At birth = naïve lymphocytes, so through childhood its really important to be exposed to antigens which matures the lymphocytes
- When lymphocytes recognize an antigen it starts dividing: clonal expansion
- First time exposure to antigen = slower & weaker response
- Subsequent exposure to same antigen: faster & stronger response
11
Q
Process of Lymphocytes
A
- Upon first exposure to a specific antigen, naïve lymphocytes reproduce
- Exposure to the antigen triggers clonal expansion & immune response
- Clonal expansion produces effector cells and memory cells
- Effector cell (B lymphocytes): immediate response and fight off pathogen by becoming plasma cells and secreting antibodies
- Memory cells: long lived and continue to reproduce so that years later when re-exposed to same antigen clonal expansion happens a lot faster
12
Q
Adaptive immunity: B-Lymphocytes
-structure
-antigen binding
- antibody functions
A
- Structure: 2 heavy chains & 2 light chains make up Y shaped structure where antigen binds to an arm of the Y, base of Y is highly conserved and the same in every B-Lymph
- Antigen binding: Y arms have specific/unique binding sites for a corresponding antigen to bind to
- Antibody functions:
1. Activate B lymphocytes
2. Act as opsonin’s to tag for phagocytosis
3. Cause antigen clumping and inactivation of bacterial toxins
4. Activate antibody dependent cellular activity like NK cells
5. Activate complement
6. Trigger mast cell degranulation
13
Q
Adaptive immunity: antibodies
A
- Antibodies recognize extracellular pathogens binding soluble or exposed antigens Like in blood or tissues
- Once a pathogen gets inside host cell, it cant be detected by humoral immune system so cytotoxic T lymphocytes defend against intracellular pathogens
14
Q
Adaptive immunity: T Lymphocytes
A
- T-lymphocytes have a T cell receptor (TCR)
- TCR are closely related to antibodies & probably share a common ancestor
- TCR bind MHC-antigen complexes on the surface of cells
- T cells cant bind to free floating antigens like B cells do
- Process
1. T lymphocytes develop during embryonic development
2. Turn into cytotoxic T cells or helper T cells
3. Cytotoxic T cells: respond to intracellular targets by killing cancerous/dysfunctional/infected cells, has MHC I
4. Helper T cells: responds to extracellular targets by binding to MHC II antigen presenting cells and secrete cytokines that activate other immune cells
5. T lymph activation: TCR bind to antigen presented on MHC receptors
15
Q
Adaptive immunity: MHC
A
- MHC = major histocompatibility complexes are membrane proteins present on every nucleated cell in the body
- MHC proteins combine with fragments of antigens that have been digested within the cells then the combined MHC-antigen complex is presented on surface of cell
- MHC I: are present on all cells, respond to intracellular targets
o CD8+ (Cytotoxic t cell) TCR binds to MHC I receptor of infected host cell - MHC II: only found on Antigen presenting cells (APC), responds to extracellular targets
o CD4+ (helper T cell) TCR binds to MHC II receptor which activates the helper T cell
16
Q
HLA: chromosome 6
A
- HLA genes are highly polymorphic and inherited in close linkage
- Linkage disequilibrium: certain alleles tend to be inherited together
- Siblings have 25% chance of inheriting the same haplotypes so often ideal donors
17
Q
HLA polymorphisms and autoimmune diseases
A
- Body attacks its own tissues mistaking them for non self-pathogens
- Genetic factors: certain mutations in genes coding for HLA have been associated with many autoimmune diseases
18
Q
Autoimmune disorders
A
- Environmental triggers
o Environmental triggers may promote the abnormal presentation of self-antigens
o Self-antigens could be modified to be recognized by the immune system = abnormal self recognition
o Cross reaction between infective agents and self agents (molecular mimicry)
o Defective immunoregulation
19
Q
Hygiene Hypothesis
A
- Proximate cause: deregulation of immune system
- Ultimate cause: hygiene hypothesis
o Lack of early exposure to full range of microbes leads to inappropriate activation of immune system
o Dysfunctional threshold between self and non self
o Manifests as autoimmune disorders, asthma, etc.
20
Q
positive and negative selection criteria
A
- MHC I is constantly presenting self-antigens
- T cells must meet these criteria for positive selection
1. Express fully functioning TCR and CD8 or CD4 proteins
2. Recognize MHC I &II complexes
3. Don’t attack self
4. Attack/recognize MHC presenting non-self-antigens - Negative selection: Death of cells if
1. Don’t express TCR
2. Don’t express CD8 or CD4
3. Don’t recognize an MHC
21
Q
Strength of recognition and +/- selection
A
- Ability to distinguish between weak and strong positive self-recognition may contribute to autoimmunity
- Weak self-antigen recognition: leads to positive selection because the cell recognizes the presented self-antigen
- No self-antigen recognition: failure of positive selection so cell dies off
- Strong self-antigen recognition: leads to negative selection because the cell recognizes MHC and kills it which means the cell is dysfunctional so the cell itself is killed too
22
Q
Trends and History of medicine and disease
A
- More hygiene and antibiotics = less exposure to pathogens = more autoimmune diseases = exaggerated immune responses leading to morbidity ans mortality
- Decrease in deaths caused by infectious diseases due to hygiene/sanitation, antibiotics, vaccines
- Deaths are caused less by infectious diseases and more so diseases related to lifestyle and diet
23
Q
Eukaryote vs Prokaryote cells for antibiotics
A
- Bacteria (prokaryotes) have a cell wall, lipopolysaccharide layer, and call membrane that eukaryotes don’t have so that can be targeted by antibiotics
- Don’t share the same DNA, antibodies, enzymes so can exploit them in antibiotics
24
Q
Bacteria classification
- 2 ways
A
- Shape
1. Bacilli – rod shape
2. Spirilla – spiral shape
3. Cocci – sphere shaped
o Staphylococci – grape like clusters
o Streptococci – in chains (strep = strip = chain) - Metabolism
1. Heterotrophs: consume others for energy
2. Photoautotrophs: make own energy through photosynthesis
3. Chemoautotrophs: make own energy from inorganic compounds
25
types of symbiotic relationships
- Mutualism: both organisms’ benefit
- Commensalism: one organism benefits while the other organism isn’t harmed
- Parasitism: one organism benefits causing harm to the other organism
- Predation: one organism benefits and the other dies
26
Mutualism
example
- E. coli is a gram negative bacteria found in the large intestines of animals
- Some strains can be pathogenic, others are habitual gut residents and provide humans with several advantages
1. Vitamin K synthesis
2. Competition with pathogenic bacteria
3. Digestion of dietary fiber
- While they receive: nutrients, a warm damp environment
27
parasitism example
- E coli bacteria can transfer genetic info through a process called bacterial conjugation (bacteria’s equivalent to sexual reproduction)
- Shigella is another gram-negative bacteria bit it’s pathogenic as it produces a toxin (shiga) that causes diarrhea
- Shigella can invade the epithelial lining of colon causing inflammation and cell death
- Shigella has transferred the genes coding for the toxin to E coli conferring pathogenicity: E coli 0157:H57
- Infection with E coli 0157:H57 can cause diarrhea (which has been selected for to flush out system)
28
bacteria and toxins
- 2 types
- Exotoxins: secreted by bacteria causing damage
o Clostridium botulinum: secretes a toxin that inhibits release of acetyl choline which block s muscle contraction so can lead to death by stopping diaphragm from contracting to breath
- Endotoxin: is a part of the bacteria itself like the cell wall
o After cell death the Lipopolysaccharides are released and are toxic to the host
29
Pathogen Virulence
- Pathogens are organisms than can cause morbidity and mortality in its host
- Pathogens do so by secreting a toxin, damaging a cell, competing for nutrients
- Virulence: ability of a pathogen to harm its host
- Trade off between virulence and transmission to another host
o High virulence needs high rate of transmission to another host because they are killing the host fast to needs a new host
o Low virulence can afford a lower transmission rate to another host because they aren’t killing the host super-fast
o High virulence = low infective dose because the pathogen replicates slowly since they do so much damage they don’t need as many replicates otherwise they would kill the host quickly
30
Discovery of Antibiotics
- Discovery of penicillin marked the dawn o antibiotic age
- Before penicillin there were natural remedies such as Vit D for the treatment of TB and Iodine for disinfection of wounds
- This means that patients could die from infections initially caused by a cold, cut, food poisoning
- Sir Alexander Fleming found out that there was a mold producing something that prevents bacterial growth which is how he discovered penicillin
- Nobel prize in 1945 for Flemming, Florey, Chain
31
Antibiotics
- Antibiotics: drugs that fight infections caused by bacteria in humans and animals
- Either kill bacteria or make it hard for them to reproduce
- They target bacteria specific structures and functions to kill them
- Antibiotics don’t work on viral infections
32
Dawn of Antibiotics: Penicillin
- Penicillin Discovered in 1928 but was medically developed and used in the 1940s by the US military to treat sick/wounded soldiers
- Used to treat various conditions: wounds, diphtheria, syphilis, TB
33
Penicillin: Structure and mode of action
- Structure: contains a Beta-lactam ring, thiazolidine ring, and a ketone side chain
- Penicillin has a similar structure to the D-Ala-D-Ala amino acids chain that holds together the peptidoglycan layer in gram + bacteria
- so it can be inserted as a substitute for one of the D-Ala which would break the bonds holding the cell wall together during cell wall formation
34
targets of Antibiotics
- antibiotics target microbial processes (structures and functions) that aren’t found in humans cellular process
- targets: folate synthesis, cell wall synthesis inhibitors, DNA gyrase inhibitors, inhibition of DNA dependent RNA polymerase, RNA synthesis inhibitors, protein synthesis (305 and 505 inhibitors)
35
Spectrum of AB activity
- not all bacteria are equally affected by antibiotics because diff antibiotics target diff bacteria
- some antibiotics are broad spectrum which means they can target many types of bacteria at once
36
Virulence and Antibiotic resistance
- AB resistance is observed within 2-4 years of the intro of new class of AB
- Bacteria have evolved and modified their virulence mechanisms to adapt to host’s defense system
- Bacteria have evolved mechanisms to resist antibiotics
1. Degradative enzymes (Beta-lactamase) = breaks down the antibiotics
2. Efflux pumps (multi-antimicrobial extrusion protein for kanamycin) = pumps antibiotics back to the outside of cell
3. Cell wall alterations (fails to bind to altered penicillin binding proteins) = modify wall structure so antibiotics is obsolete
4. Mutations on target enzymes (DNA polymerase site bound by quinolone antibodies) = modify self so not targeted by antibiotics anymore or their specific feature
37
AMR: MRSA
- MRSA: methicillin resistant staphylococcus aureus
- Problem: bacteria has evolved to survive common antibiotics
- Seen in hospitals around 1960 but entered wider community in 90s
38
Ways AB resistance can spread
- Hospitals
- Animal products
- Agriculture
- Ocean
- Treatment plants
- Tourism and food transports
39
Antibiotic resistance is a global health concern
- First bacteria to be resistant to all known antibiotics was discovered in 2017
- Drug resistant staphylococci, enterococci, streptococci are the major pathogens that increase morbidity, mortality, health care costs
- Arms race – coevolution – new AB and new AB resistant strains of bacteria
- WHO predicts 10 mill AB resistance related deaths each year by 2050
40
Antibiotic Drug Resistance index
- DRI is a measure of the ability of AB to treat infections and the extent of their clinical use
- Due to poor public health systems, OTC sale, infection rates
- High DRI = poor efficacy
- Should limit antibiotic use because predict increases in resistance and death
- Predict more deaths due to AB resistance than cancer by 2050
41
Antibiotic use and safety
-side effects
- Recent studies show that long term use of certain AB may have debilitating health affects
- Side effects of Fluoroquinolones
1. Tendonitis
2. Neuropsychiatric disorders
3. Hypoglycemia – diabetes
4. Neuropathy
5. Yeast infections
42
Natural selection and antibiotic resistance
- Antibiotic resistance is a clear case of natural selection
- Overuse through unnecessary prescribing or antibiotics is the major cause of antibiotic resistance
- Every time you give AB = you promote growth/selection of resistant bacteria
43
Evolutionary Perspective of AB
-7 ways to slow AB resitance
- AB use drives the evolution of AB resistance
- Judicious use of AB can slow the spreading or AMR
1. Dont treat asymptomatic infections
2. Use AB only when they can work
3. Use as little as possible
4. Decrease the need to AB treatments by taking preventive measures like hygiene, vaccination, isolation of infection
5. Prevent non medical use of AB
6. When needed use in combo therapy = use many AB at once to make sure you kill every single bacteria
7. Take AB only after 2 weeks of sickness
44
Non-Antibiotic treatments against drug resistant infections
- Stem cell AMPs
- Vaccines
- Nanobiotics, enzybiotics
- Fecal microbiota transplantation
- Phage therapy
- Immunotherapy
- CRISPR-Cas/editors
- Probiotics/microbial therapies
