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Cellular and Humoral response:
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Cellular response: relates to endogenous antigens, is a T-cell mediated response, involves Th1 t-helper cells and cells like natural killer
cells
...

Humoral response: relates to exogenous antigens, involves B-cells but also Th2 T-helper cells and some effector cells
...

The cellular immune response involves 2 responses: 1
...
The delayed type hypersensitivity response which causes an inflammatory response
mediated by T-dth cells (T-delayed type hypersensitivity cells)
...
Nucleated cells are all cells of the body except erythrocytes
...
Processing is carried out by
the professional antigen presenting cells (like macrophages and dendritic cells) for class II MHC or any nucleated cell for class I
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MHC presents antigens to T-cells via a tri-protein complex (trimer)
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The lysosome containing vesicle
fuses with the antigen containing endosome and therefore the antigen is digested to form peptides
...
An invariant chain forms a complex
with a MHC II molecule and allows it to move out of the endoplasmic reticulum in a vesicle
...
As a result, cathepsins digest the invariant chain to
form CLIP
...
The peptide containing MHC-II moves through
the golgi apparatus to the plasma membrane in a vesicle and therefore the MHC-II and the peptide are expressed on the cell’s surface
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MHC-II molecules consist of α and β polypeptide chains and a groove a molecule to bind
...

Endogenous pathway: proteasome causes proteolysis of the cytoplasmic proteins causing formation of peptides
...
MHC
class I molecules are formed by ribosomes in the endoplasmic reticulum – by binding together the MHC α chain, calreticulin (a
chaperone), tapasin (TAP associated glycoprotein), and beta-2-microglobulin
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Therefore the peptide is added to MHC-I and are both then
expressed on the cells surface
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Endogenous pathway allows CD8 Cytotoxic T-cells to interact
with MHC-I
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Interaction of T-cell receptors with MHC and antigen: Interactions that allow antigen presentation include: 1
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ICAM1 (intracellular adhesion molecule) on antigen presenting cells bind to LFA1 (lymphocyte functional antigen) on T-cell, 3
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CD28 on T-cell binds to B71/B7-2 on antigen presenting cells
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CD28 is a critical receptor for B7-1 and B7-2 before stimulation
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Antigen presenting cells secrete interleukin-1 (a cytokine that activates leykocytes), interleukin-6, TNFα (tumour necrosis factor),
interleukin-12, and interleukin-15
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Naïve cells are those which are meeting an antigen for the first time
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Naïve T-cells NEED MHC restricted antigen + B7-CD28 costimulation + interleukin 1 from antigen presenting cells
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Effector T-cells have
less need for B7-CD28 and interleukin 1, these cells show CD40RO on their surface plus lots of adhesion molecules (LFA1-CD2), they
are capable of killing targets by direct contact, and are found in sites of inflammation and active lymphoid tissue
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When the T-cell is activated it becomes an effector cell
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TCR communicates with nucleus, when it is stimulated by MHC restricted
antigen via IP3 pathway – leads to interleukin-2 production
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Antigen presenting cells are activated by T-cells in a process called licensing – so that they can present to T-cytotoxic cells
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Licensing involves Cytotoxic T-cells and Th1 cells interacting with
antigen presenting cells
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Interleukin-2 and antigen presented by licensed antigen
presenting cells cause the naïve Cytotoxic T-cell to become effector Cytotoxic T-cells which kill antigen presenting cells associated with
MHC-I
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These granules consist of perforins and granzymes
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Granzymes interact with the target cell to initiate apoptosis
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Cytotoxic T-cells can also kill target cells using Fas-Fas ligand pathway
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When these bind they activate caspases in the target cell which initiate apoptosis
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Virally infected cells down
regulate MHC-I
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Natural killer cells and NKT cells are non-antigen specific killer cells
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The target cell is killed by macrophages, neutrophils, eosinophils and natural killer
cells using perforins, granzymes, lytic enzymes and TNF
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Humoral (B-cell) response: B-cell activation so antibodies can be formed
...

B-1: less common form, found in body cavities, long life, poor class switch, no memory cells, do NOT need T-cell help, and have
restricted antibody diversity
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2 types of B-cell responses: Thymus dependent response (this response required T cell help), and Thymus independent response
...
B-cells
can act as antigen presenting cells and present antigen for which they produce the antibody – this occurs due to surface IgM mediated
phagocytosis and antigen processing to MHC-II
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Class switching depends on cytokines produced by the plasma cell: if interleukin4 is produced the plasma cell produces IgE, if TGF-β the
plasma cell produces IgA, if IFN-gamma the plasma cell produces IgG
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It is NOT antigen specific and has NO
memory
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Innate system is involved in inflammation
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Type 1 interferons are divided into α and β types
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IFN’s function by inhibition of viral transcription, degradation of viral DNA, activation of natural killer cells and also up-regulation of
proteasome activity
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C-reactive protein binds to
some bacteria via surface phospholipids and stimulates both phagocytosis and complement activation – marker for inflammation
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We have evolved ligands which recognize them – these ligands
are pattern recognition molecules (PRM’s) which can initiate inflammation
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Toll-like receptors are membrane bound PRN’s and recognise both bacterial and viral PAMPs
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Complement: a cascade of enzymes resulting in a membrane-attack-complex (MAC) which creates holes in the membrane, also
anaphylotoxins which promote inflammation, and bound C3B which opsonises cells
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Activated
by antibody to antigen – CLASSICAL PATHWAY, 2
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Activated by mannose binding lectin (MBL) – LECTIN PATHWAY
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What stimulates phagocytosis? Negatively charged particles, opsonisation (coating of targets with antibody or complement which is
detected by phagocytes via receptors – Ab Fc receptors and C3 receptors), and Pattern recognition molecules (specific molecular
patterns on bacterial membranes)
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Mucin like CAMs, 2
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Ig-like CAMS (ICAMs), 4
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Mucin like CAMS bind to selectins
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Rolling-activation-migration is seen when white cells approach
capillary walls and is controlled by ICAM pairs
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Immunological cells are attracted to sites of inflammation by chemokines which react with
chemokine receptors on white cell surfaces – CCR or CXCR types
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Chemokines are upregulated by the
cytokines – gamma-interferon and TNF-α
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Hypersensitivity:
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Gell and Coombs Classification – classifies immune disease of seemingly inappropriate immune response (hypersensitivities) by
immunological reaction involved
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Atopic = people with a predisposition to allergy
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Upon first meeting the allergy no reaction occurs – priming dose
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Immunological reactions involve mast cells and IgE isotype of antibody
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Example = bee sting or hayfever
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In
atopic individuals, IgE is formed which binds to mast cell IgE Fc receptors in the tissues – produces no response
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Mast cells release primary mediators immediately and
secondary mediators more slowly
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Primary mediators = histamine, serotonin, and
heparin
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Primary mediators are stored in granules and secondary are
manufactured during degranulation
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Histamine is stored in granules as an ionic complex with heparin
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Reasons for atopy: defective IgA production, defective IgE production or class switch, defective Tregulatory cell populations, or use of certain drugs
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Damage is via complement activation and cell lysis
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Example = myasthenia gravis
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The soluble antigen can be autoimmune or non-self antigen (a bacterial antigen)
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Example = rheumatoid arthritis
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Only type which is caused by a cell mediated response with involvement of Th1, macrophages and Tcyt cells but NOT
antibody
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Damage is via Tcyt cell and macrophage activity
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Type 5: an antibody response to a cell surface receptor which is capable of acting as an agonist
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Transplant immunology: usually involves a cell mediated response
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Allergen molecule characteristics: heterologous protein and peptide, small molecules which act as haptens, can be drugs like penicillin
or food
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Non-seasonal: moulds, feathers

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Detection of allergy specific allergens: skin prick test where a range of purifies common allergens are placed in solution on the skin
and is scratched in
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Contact dermatitis patch – distinguishes irritant from allergic
response
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Superantigens are bacterial or viral proteins, they can bind to MHC class II molecules and T-cell
receptors
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Cross linking leads to activation of T-cell and
antigen presenting cell and results in oversecretion of cytokines
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Active vaccine – induces an immune response and memory cells and gives long term protection
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Heat is NOT used since it will disrupt the epitope
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Live vaccine: an attenuated strain of bacterium or virus
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Strong response and good memory
and both antibody and cellular response are produced
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Pathogen: a microorganism that parasitizes an animal
or human and produces a disease
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Infectiousness: the ease with which a pathogen can spread in a population
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Virulence: the
measurement of a pathogens ability to cause severe disease
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Outbreak: an occurrence of disease clearly in excess of normal expectancy
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Vector: a living creature that can transmit infection from one host to another
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Types of bacterial infections: opportunistic – caused by indigenous flora or transient bacteria if the host defences are compromised
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Secondary- microbial invasion subsequent to primary infection
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Normal Flora: are microorganisms which inhabit surfaces of the body and do not cause disease in their normal environment however,
they are potentially pathogenic if they enter other body sites
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Normal flora can be
derived from: skin, air, genital tract, mouth/pharynx, and environment/food
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Normal flora of the skin = staphylococci, streptococci, candida
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Normal flora of the GI tract = E
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Normal flora of the perineum and urethra =
mycoplasmas
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Staphylococci on the skin is adapted to dry conditions, and high salt
conditions from sweat
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The beneficial effects of normal flora include: synthesis and
excretion of vitamins, prevention of colonisation by pathogens (colonisation resistance), production of substances inhibitory to other
bacteria, stimulation of tissue development, stimulation of production of cross-reactive antibodies
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Staphylococcus epidermidis causes bloodstream infections due to
catheters but it is usually non-pathogenic
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coli causes UTI’s
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7 steps of infection cycle of pathogenic bacteria: maintain a reservoir (somewhere to live before and after infection), transport to the
host, adhere to + colonise + invade host, initially evade host defences, multiply in host cells or its cells, can damage the host, leave the
host and return to reservoir or enter a new host
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Microorganisms that resist drying spread more rapidly in the
environment
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Staphylococci are stable to drying and
Neisseria meningitidis is unstable
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Examples of transmission by venereal route: gonorrhoea caused by Neisseria gonorrhoeae, and syphilis
caused by treponema pallidum
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Examples of transmission by exhalation of droplets: TB is caused by mycobacterium
tuberculosis, streptococcal infections caused by streptococcus pyogenes, and diphtheria caused by corynebacterium diphtheriae
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Transmission by a fomite: an inanimate object that serves as an intermediate for transmission of infection – examples are needles and
towels
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Main entry sites of pathogen =respiratory tract, mouth/GI tract, skin,
genital tract
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Lysozymes break down β-(1-4)-glycosidic bonds between Nacetylmuramic acid and N-acetylglucosamine in peptidoglycan
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Adhesins allow pathogens to adhere to epithelial cells on
mucous membranes of respiratory, alimentary and genitourinary tract
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Factor
Effect
Organisms
Hyaluronidase
Dissolves hyaluronic acid in connective
Streptococci, staphylococci, pneumococci
tissue
Deoxyribonuclease
Lowers viscosity of exudates allowing the
Streptococci, staphylococci, clostridium
pathogen more mobility
perfringens
...


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Toxigenicity = ability of an organism to produce a toxin
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Intoxication=disease resulting from entry of a preformed toxin into the host
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2 types of bacterial toxins: Endotoxins and Exotoxins
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Endotoxins can cause gram negative
septicaemia since Neisseria multiples in the blood, endotoxins cause widespread movement of rash in septicaemia
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Exotoxins are toxic substances usually excreted by the organism and is therefore not a structural component, it is a protein and is
denatured at high temperatures (60-80 degrees), is found in gram positive and negative cells, don’t cause fever, highly toxic
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Examples of disease caused by exotoxins are botulism and diphtheria
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Pore formers disrupt integrity of plasma membrane, haemolysins release haemoglobin from RBC’s, leukoacidin destroys phagocytic
leukocytes, leucithinases/phospholipases attack phospholipid of host cytoplasmic membrane
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Membrane disrupting toxins
examples: C
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Neurotoxins can act as proteases
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Tetanospasmin causes static paralysis
(permanent muscle contraction) as it prevents muscle relaxation, lockjaw is a common symptom
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The spores gain entry to the body through wounds
which could be caused from gardening or a car crash
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In normal muscle contraction, the acetylcholine signal is received by the muscle and the muscle contracts in response
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An inhibitory interneurone releases glycine which is an inhibitor of acetylcholine release therefore no acetylcholine signal is received
by the muscle and so the muscle relaxes
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BOTOX is a highly diluted and highly purified form of Botulinum toxin A
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Botulinum toxin is an A-B toxin
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In botulism the toxin is not produced in the
body, the preformed toxin is ingested from inadequately sterilised or canned foods
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Enterotoxins are exotoxins which act on the intestine
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Cholera is a second messenger pathway disruptor
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Cholera is caused by poor sanitation and
contaminated food/water
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Toxin production occurs when the organism has
adhered to the small intestine
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Pathogenicity factors of cholera = mucinase
which allows the organism to adhere to the intestinal wall, mucinase also breaks down mucus
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The B region is made of 5 subunits and contains site through which the toxin combines with the epithelial cytoplasmic membrane
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So B enables the toxin to attach
to the cell initially by interacting with a gangliocide GM1 receptor on the cells surface
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A1
causes toxic activity and therefore symptoms
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So A1 causes ADP ribosylation of G proteins and therefore
inhibits the activity of the GTPase
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The loss of water causes
blood to become more concentrated, causes dehydration and diarrhoea
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Diarrhoea causes the spread of the organism so more is ingested – this allows the survival of the species
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Toxin inhibits GTPase activity
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Cholera
produces labile and stable toxin
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coli: EPEC (enteropathogenic E
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ETEC (enterotoxigenic E
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EHEC
(enterohaemorrhagic E
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coli 0157, is invasive to cells and therefore causes bloody diarrhoea, mucosal damage and
haemorrhage, the kidneys have receptors for toxins and so can cause haemolytic uraemic syndrome
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coli
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coli
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coli
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coli pathogenicity factors: capsular K antigens, fimbriae, LPS O antigen, enterotoxins, verocytotoxin which causes kidney damage,
enteroadherence, enteropathogenic E
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Pharmacokinetics – handling of the drug within the body and includes ADME
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Concentration dependent antibiotics: bactericidal effect related to peak concentration at site of infection
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Examples include aminoglycosides and quinolones
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Little
or no post antibacterial effect
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Aminoglycosides are synergistic with penicillins and glycopeptides
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Penicillins and glycopeptides disrupt cell wall synthesis and so increase penetration of aminoglycosides to the site of action
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Glycopeptides can be used to treat C
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Glycopeptide example = vancomycin
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Interaction = macrolide and simvastatin
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Interaction = macrolide and warfarin
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Adipose tissue can secrete adipokines and cytokines
which have a role in inflammation
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Hydrophilic antibiotics include β-lactams, glycopeptides, aminoglycosides, polymixins, and carbapenems
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β-lactams - time dependent kill,
Aminoglycosides – concentration dependent kill, and Vancomycin – time dependent kill
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Fungi are saprophytic organisms so they
break down tissue and recycle organic matter
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Fungal cell wall is made of chitin which is a polymer of N-acetyl-glucosamine
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Four main groups of fungi: yeasts, yeast-like fungi, dimorphic fungi, filamentous
fungi
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Example=Cryptococcus neoformans which is a pathogenic yeast, that has a polysaccharide capsule,
reproduces by budding, is the only species of Cryptococcus that can grow at 37 degrees, and causes cryptococcosis – an infection that
occurs by inhalation and through skin
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Candida is microflora and can be increased due to antibiotics which will causes
candidiasis (thrush) – an infection of the mouth, lungs and intestinal tract
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Dimorphic fungi: at 22 degrees grow as a filamentous form and at 37 degrees grow in yeast form
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Filamentous fungi: are multicellular moulds which grow as hyphae
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Lower fungi produce non-septate hyphae which are hyphae that do not have cross walls, higher fungi produce septate
hyphae which do have cross walls
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Dermatophyte infections produce tinea infections and affect keratinised
areas of the body – skin, nails and hair
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The spore
germinates and penetrates the stratum corneum
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Mucormycosis =
infections caused by zygomycetes like mucor and rhizopus
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Vegetative reproduction (Asexual reproduction): does not involve the union of nuclei and the progeny are identical
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Binary fission: parent cell divides to form 2 identical daughter cells
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Budding: typical of yeast cells, progeny
occur as a small bud from the parent
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Fragmentation: hyphae break up into components called arthroconidia
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Formation of spores
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Contamination can lead to production of alfatoxins which are mycotoxins
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Aspergillus niger can cause aspergillosis – infection of lung
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The conidia at the end of the conidiophores are pigmented – black with a white reverse
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Polyene macrolides are antifungal drugs which bind to ergosterols in fungal cell membranes and hence affect membrane permeability
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They form pores in the membrane leading to increased loss of metal ions (like sodium, potassium,
calcium and magnesium)
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Macrolides can be used against organisms that contain sterols like
yeasts, protozoa and filamentous fungi
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Amphotericin B is used
systemically, is highly protein bound, and is formulated with lipids to increase solubility, stability and absorption (so they are
encapsulated in liposomes)
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Polyene macrolides are the most toxic antifungals since they can affect host
cells
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Nystatin is VERY
toxic
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Amphotericin B and Nystatin contain lactone rings, a hydrophobic region = polyene chromophores, and a hydrophilic
region = hydroxyl groups
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Natamycin is a polyene macrolide derived from Streptomyces natalenis and has a 26-membered lactone ring
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Polyene macrolides can stimulate release of cytokines and
therefore produce an inflammatory response
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So amphotericin B and Nystatin can be used Filipin cannot be used since it is too toxic
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Polyene macrolides side effects = disturbances in
renal function, renal toxicity, anaphylaxis and liver toxicity
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Allylamines and thiocarbamates are antifungals which inhibit biosynthesis of ergosterol via inhibiton of squalene epoxidase enzyme
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Thiocarbamates are used to treat Dermatophyte infections and have no activity against candida
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Azoles are antifungals and there are 2 groups – Imidazoles (Clotrimazole, ketoconazole and miconazole), and Triazoles (Fluconazole,
itraconazole, viroconazole)
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Depletion of ergosterol in fungal membrane disrupts the structure of the membrane
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Azole resistance in fungi occurs by: increased levels of the cellular target CYP450 lanosterol 14-α-deaminase, decreased affinity of
azoles for cellular target, and upregulation of genes controlling drug efflux
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Azoles are fungistatic at MIC’s
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First generation =broad
spectrum of activity, are lipophilic and therefore have poor water solubility, are used in topically
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Clotrimazole – is a topical agent, which is fungistatic but may be fungicidal at higher concentrations, and is used to treat
candidiasis
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2nd generation: Ketoconazole has improved
bioavailability and water solubility and is therefore orally active and can be used for GI infections, it is used to treat Dermatophyte
infections
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Resistance occurs due to increased levels of cellular target and efflux of drug (cannot
achieve therapeutic levels in cells)
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Fluconazole is used to treat candidiasis, has poor activity against aspergillus
species
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Flourinated pyrimidines are nucleoside or base analogues – and so they resemble natural nucleosides or bases, however they cannot
take part in normal DNA replication or RNA synthesis
...
Example = flucytosine
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Flucytosine is
fungistatic and fungicidal
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Griseofulvin: is a fungistatic antibiotic produced by penicillium griseofulvum
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Griseofulvin inhibits mitosis in metaphase, it binds with microtubules of the mitotic spindle, interfering with their assembly
and function
...
They are semi-synthetic lipopeptides which inhibit synthesis of
β(1-3) D-glucan a unique target in fungal cell walls
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Echinocandins have good
activity against candida and aspergillus
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It is
good against candida and Cryptococcus and neoformans
...
Cryptococcus is treated using amphotericin and
flucytosine
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Which categories of medicines (dosage forms) are vulnerable to fungal growth and why? Medicines that contain/absorb water are
vulnerable to fungal growth
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Creams and lotions
are vulnerable to fungal growth
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How can fungal growth be prevented? Fungal growth can be prevented by altering pH, removing water or by adding chemical
preservatives
...

Vaccines are medications designed to stimulate the immune system to generate a response that will protect the individual from
disease by a specific pathogen
...

Active immunity: occurs by body’s immunological defence mechanisms following exposure to an antigen
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Vaccination: the induction of active immunity by introducing microorganisms or their products into the body
...

Immunoglobulins are made from plasma and are of human origin
...
Toxoids are toxins which have been
modified usually by formalin to remove toxicity without affective immunogenicity – they can still illicit an immune response but are no
longer harmful
...
Inactivated=dead
...
Vaccination educates the immune system and primes it to recognise pathogens that cause a
particular disease
...
Response to vaccine or natural encounter with pathogen=primary response
...
Vaccines can cause humoral immunity which is the
component of the immune system involving the transformation of B cells into plasma cells that produce antibodies to a specific
antigen
...
tuberculosis
...
A vaccine must
therefore stimulate a cell mediated immune response
...
Cell mediated immunity is the component of the immune system that involves T lymphocytes and not
antibodies from B lymphocytes
...

Advantages of live vaccines: mimics natural infections so more effective, and exposure is through the natural route (orally) therefore is
more appropriate
...

Advantages of killed vaccines: no chance of infection
...

Small pox: variolla major virus is from poxviridae family
...
It enters through the respiratory tract and multiples in
lymph nodes and then the spleen
...

Attenuated vaccines are formed due to subcultivation
...
Viruses are NOT
genetically manipulated but have been passaged until they lose some virulence properties
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Host range attenuation: 1
...
vius is incubated on cells from another
host (like a monkey), 3
...
Virus can be used as a vaccine as it cannot grow on
human cells
...
The organism is dead so it does not induce production of sufficient antigen to provide
protection
...
Adjuvants (like oil emulsions) can be used to
enhance the immune response to an antigen and improve vaccine efficacy
...

Polio is a small ssRNA virus which belongs to the picornavirus family group 4
...

Sabin and Salk polio virus: Salk developed an injectable formaldehyde killed vaccine and Sabin produced a live attenuated polio
vaccine for oral administration
...
Advantages: prevents replication of polio virus in the GI tract and therefore provides local
immunity, it is easily administered, provides lasting immunity with 2 doses, is removed in faeces and results in passive immunisation
of others
...

Salk- inactivated/killed vaccine
...
Disadvantages: it does NOT stimulate
mucosal immunity – so it does not prevent viral replication in the GI tract, it requires 4 doses, and must be administered by
professionals
...
Sabin vaccine induces production of IgA
...
The virus particles are disrupted using surfactants
...
Bacterial cell component vaccines – consist of components of
bacterial cells
...
The
likelihood of adverse effects is reduced
...
influenza and Neisseria
...
DNA encodes genes for antigens relevant to a
particular infection and so generates immunity to a pathogen
...

Jenners method of using cowpox infection to confer immunity to smallpox was superior to earlier methods because is carried a
significantly lower risk of serious disease
...

The Pasteur method for treating rabies consists of a series of inoculations with attenuated rabies virus
...
IgA is passed in milk from mother to infant
...
Development of live attenuated strains through genetic manipulation and involves the deletion of
selected genes from bacterial genomes to generate strains with reduced virulence
...
Development of multivalent vaccines through
genetic manipulation and involves generating vaccine which protect against multiple pathogens
...
Production of vaccines in plants
...

Anti-idiotype antibody vaccines
...
Peptide vaccines – stimulate T-cell responses
...
Skin functions: protective barrier against mechanical, thermal and physical injury
and hazardous substances, prevents loss of moisture, reduces harmful effects of UV radiation, acts as a sensory organ, helps regulate
temperature, and production of vitamin D
...
Basal cells divide to become prickle cells
and this then becomes the stratum corneum via keratinisation
...
Glands in skin
include eccrine sweat glands and apocrine glands
...
It secretes sebum
(triglycerides, fatty acids and cholesterol)
...

Control of microbial population: 1
...
pH – normal pH between 4
...
5, acidity is due to
fatty acid secretions and can inhibit bacteria, 3
...

Skin turnover/resident microflora – resident microflora occupy most of the available space and nutrients, and also skin is
continuously shed and so it is harder for transient bacteria to adapt to the environment in the short time before shedding
...
Small, flat, red spots showing local inflammation
...
2
...
3
...
4
...
5
...
6
...

Common skin infections: 1
...
2
...
3
...
4
...
Features of acne: comedones (black and white
heads), inflamed sports and seborrhoea
...

Ducts become blocked by dead skin cells
...
A blackhead (open comedone) is present
as a black lesion due to melanin
...
Seborrhoea = excessively
greasy skin and is caused by an increase in the rate of sebum production and an increase in the size of the sebaceous glands
...

Superficial spreading infections of the skin: 1
...
Treatment can be topical – bacitracin, fusidic acid or systemic – penicillin, ampicillin, erythromycin
...
Scalded
skin syndrome: caused by staphylococcus aureus producing exfoliatin toxin
...
3
...
4
...

Necrotising infection – an infection of deep layers of skin and subcutaneous tissue and causes necrosis of superficial fascia
...
Risk factors for type 1 = diabetes, old age, surgery, chronic skin infection and immune
system impairment
...

Respiratory tract infections: Infection - is present in an individual when microorganisms act as irritants and cause an obvious host
reaction
...
Corynebacterium is a gram positive rod
...
α-haemolytic streptococci is
microflora of the nasopharynx and the colonies are surrounded by a greenish zone when grown on blood agar
...

Defence mechanisms of the respiratory tract: 1
...
Adenoids and tonsils are lymphoid
organs of the upper respiratory tract, pathogens and particles impinge on these lymphoid tissues
...
Tracheobronchial secretions:

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Bronchial secretions contain several antibacterial substances - Lysozyme
...
Usual function: cell lysis, prepares viruses and bacteria for opsonisation, and activates phagocytes
...
Tracheobronchial secretions also contain secretory immunoglobulins and
defensins
...
4
...
Mucociliary transport – mucus is composed of high molecular weight glycoproteins, it provides a physical barrier against
microbed and is also impermeable to water so it prevents dehydration
...
Impairment of mucociliary transport is due to surgery, viral infection, bacterial and
fungal toxins and also antibiotics
...
In
bacterial infections the higher viscosity and elasticity of hypersecreted mucus leads to reduced mucociliary transport
...
Cough and 7
...

Cystic fibrosis involves abnormal chloride transport across the apical cell membrane of the epithelial cells which leads to decreased
water secretion resulting in thick viscous and adherent secretions that facilitate bacterial colonisation
...
Increased amounts of thick mucus result in an increased inflammatory
response in the mucosa leading to decreased mucociliary clearance and further thickening of the mucus
...

Rhinovirus is a lytic ssRNA virus that binds to CD45 receptors on respiratory epithelial cells
...

Lower respiratory tract infections: pneumonia = inflammation of the lungs, bronchitis = inflammation of the bronchi, bronchiolitis =
inflammation of the bronchioles, Bronchiectasis = pathological dilation of bronchi due to weakened bronchial walls, and croup –
inflammation of the larynx and trachea
...
influenzae
...
Cystic fibrosis is caused by Pseudomonas Aeruginosa which forms a biofilm in the lungs
...
Tuberculosis predisposing factors = age malnutrition, alcoholism,
immunodeficiency, and poor living conditions
...
Treatment – initial phase (2 months) –
isoniazid, rifampicin, pyrazinamide and ethambutol
...
Monitoring = liver function
test, renal function test and eye tests
...
influenzae and S
...

Antimicrobial use: Advantages of combination therapy = reduction in the likelihood of drug resistance, provide synergy, improved
survival, wide spectrum
...

Viruses: are static structures so they have NO metabolic activity of their own and so they rely on the host biosynthetic machinery for
protein synthesis
...
Viruses contain viral genome in a protein coat – either DNA or RNA
...
DNA viruses include HepB and herpes simplex
...
Sulphonamides
and trimethoprim inhibit folate synthesis and are inactive against anaerobes
...
Rifampicin
inhibits RNA synthesis and its used against gram positive organisms
...
Linezolid – is an oxazolidinone antibacterial which is active against gram positive organisms and is
used for MRSA and VRE
...
Risk factors of TB: extremes
of age, HIV, cancer, diabetes, malnutrition, and end stage renal disease
...

Treatment: sterilising antibiotics like rifampicin which kill actively growing and dormant bacteria, potentially bactericidal antibiotics
like isoniazid and ethambutol which kill actively diving bacteria, and also bacteriostatic antibiotics
...
Steroids reduce fibrosis (scarring) during healing
...
difficile causes diarrhoea which can be treated using vancomycin
...
Trimethoprim is used
for UTI’s
...
Other information needed = allergy status
and details, if patient is pregnant, if the patient has had recent contact with animals, if the patient has travelled recently, if the cough is
productive, antibiotics taken, full drug history and compliance to medicines
...

Contamination=transient presence of microbes
...
Infection = damage of tissues by
microbes
...
Normal flora = microbes that co-exist with humans
...
Progress of clinical symptoms: SIRS (systemic
inflammatory response system) to sepsis to severe sepsis to septic shock
...
Stimulation of the host immune response by microbial toxins causes an
inflammatory response that can lead to endothelial damage
...
In sepsis the imbalance between the pro-inflammatory cytokines and antiinflammatory mediators result in: stimulated coagulation response, inhibited anticoagulant response, inhibited fibrinolytic response
...
In sepsis the ability to down-regulate inflammatory response to infectionis lost
...
Role of
endothelium = interaction with leukocytes, release of cytokines and inflammatory mediators, release of mediators of vasodilation and
vasoconstriction and also allows clot formation
...
Normally the endothelium down-regulates pro-inflammatory response
by expressing anti-inflammatory and anticoagulant mediators
...
Initiation of coagulation occurs by the extrinsic and intrinsic pathway
which leads to a common pathway
...
The intrinsic
pathway is slower and involves mediators that are already present in plasma
...
Activated factor 10
combines with factor 5 in the presence of calcium ions to form prothrombinase
...
Thrombin and calcium ions then catalyse the conversion of fibrinogen to fibrin – leading to clot formation
...
Severe sepsis is a procoagulant state
associated with reduced fibrinolysis
...

Monitor white cell count, C reactive protein, erythrocyte sedimentation rate
...
Patients who
develop sepsis are immunosuppressed
...
Investigations for
severe sepsis = FBC (RBC count, haemoglobin, haematocrit, WBC count, platelet count), clotting tests (pT, aPTT), arterial blood gas,
serum electrolytes, glucose, LFT, urine analysis and ECG
...
Poor prognostic
indicators: increased pT + aPTT + D-dimer and IL-6, low levels of antithrombin and patient may have thrombocytopenia
...
There are 5 mechanisms of
resistance: 1
...
Modification of the cellular target, 3
...
Modification
of cell wall resulting in decreased antibiotic permeability, 4
...
Changes in gene expression/metabolic
bypass
...
Innate or intrinsic resistance – is resistance which may be
attributed to the normal structure or other properties of the cell, it includes factors that prevent uptake of the antibiotic such as
impermeability of the cell AND also lack of cellular targets or altered target structure
...

Acquired resistance – is resistance in an organism that was previously susceptible to a particular antibiotic
...
Resistance to β-lactams may be acquired through: altered gene expression,
alteration to target sites due to mutation of penicillin binding proteins, or changes in membrane permeability
...

1
...
Inactivation of β-lactam antibiotics like penicillins and cephalosporins
by β-lactamase
...
Most classes of β-lactamases use a serine
ester hydrolase or a zinc ion to attack the ring
...


3
...
Chloramphenicol acetyl transferase (CAT) modifies chloramphenicol by attaching an acetyl
group from acetyl coenzyme A
...
Aminoglycosides such
as neomycin block protein synthesis by interacting with ribosomes and preventing the formation of an initiation complex
...
Aminoglycosides can
be modifies by aminoglycoside acetyl transferase
...
It is ALWAYS acquired resistance and it may arise through mutation or horizontal gene transfer
...
Horizontal gene transfer allows resistance
...
Genes for vancomycin resistance result in the production of modified precursors to which vancomycin cannot bind
...


Metabolic bypass/changes in gene expression: Over expression of existing genes results in an increased abundance of target
proteins to a level where clinically achievable concentrations of antibiotic cannot act effectively
...
Resistance to trimethoprim may arise by metabolic bypass which is the acquisition of new copies of DHFR which are
resistant or less susceptible to trimethoprim or due to changes in expression of DHFR leading to the production of levels that outcompete the antibiotic
...

4
...
Examples of antibiotic resistance due to efflux =
tetracycline resistance
...
Pseudomonas aeruginosa is
resistant to β-lactams since efflux pumps can extrude β-lactams out of the cell
...
P
...
MexB – an energy dependent pump at the inner membrane
...

OprM – outer membrane protein
...
MexA – links OprM with MexB
...

Spread of antibiotic resistance: antibiotic resistance genes are spread by 3 main genetic elements – plasmids, transposons, and
integrons
...
There are 2 types of plasmids – conjugative plasmids which allow
cell to cell transfer of genetic information, and mobilisable plasmids which cannot start conjugation but can move when other plasmids
set up a conjugation apparatus
...
coli = fertility factor (F-factor)
...

This can then be moved between cells that are infected
...
Specialised
transduction where only specific genes closely linked to the bacteriophage are transferred, it involves site specific recombination, 2
...
Bacteriophage T4 undertakes generalised transduction
...
Phage P22 DNA infects a host cell and makes subunit components for more phage, the DNA is packaged into the capsid head, the
assembly of the new phage is completed and then the phage is released when the cell lyses, the transducing phage particles then inject
host DNA into the new cell where it recombines into the chromosome
...
coli phage lambda: it
undertakes a lysogenic phase, the phage genome is integrated into the host cell chromosome, when the phage is excised from the
genome, regions of host DNA may also be excised and appended to the phage genome
...
Genes are encoded by gene cassettes which are integrated and excised by the integrin integrase
enzyme (so integrates excised genes)
...
Transposons are mobile
genetic elements which integrate into the chromosome at random points and readily between DNA molecules
...


Genes for transposition reside on IS elements
...
Overall, IS elements contain transposons and transposons move DNA from
one location to another
...

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Respiratory Syncytial Virus (RSV): is a paramyxovirus, has an ssRNA genome enclosed in protein envelope
...
Glycoprotein mediates the attachment to host
cell receptor
...
F glycoprotein also induces fusion of infected cells resulting in
syncytium formation – these are multi-nucleated giant cells
...
RSV replicates in ciliated
epithelial cells of middle and lower respiratory tract
...
RSV
releases enzymes which activate complement and initiate a local inflammatory response
...
F glycoprotein is only present on the surface membrane of the virus
...
2 drugs used to treat RSV are: Ribavirin and Palivizumab
...
Ribavirin is used for bronchiolitis caused by RSV
...
Taribavirin is a ribavirin derivative – it’s a 3-carboxamidine derivative of the parent 3-carboxamide
...
Palivizumab is a humanised mouse monoclonal antibody (IgG) – composed of human and murine
antibody sequences
...
Activity is directed against an epitope in the antigenic site of the F protein on the outer
surface of RSV
...
It is used
for prevention of lower respiratory tract diseases caused by RSV
...
Hepatitis A virus (HAV) is ssRNA (HAV vaccines are based on formaldehyde inactivated virus) and Hepatitis B virus
(HBV) is a DNA virus (partial dsDNA)
...
The HBV vaccine is based on recombinant hepatitis B surface antigen
...
Chronic hepatitis B is treated using nucleos(t)ide analogues and Interferon-α
...
Interferon-α is a cytokine produces by host cells in vivo called plasmacytoid dendritic cells
(DC’s)
...

IFN-α/β also activates CD8+ T cells which produce more IFN-ϒ which kills the infected cell
...
HCV chemotherapy – pegylated interferon-α and ribavirin
...
Antiviral chemotherapy tries to exploit the differences that exist
between viral and host cells and involves targets unique to the virus, the target in the virus is similar but NOT identical to host cell,
target in virus is shared by the host cell
...
Herpes simplex type 1 = cold sores,
herpes simplex type 2 = genital herpes and varicella zoster = chicken pox
...
There are 2 receptors on the lymphocyte surface that HIV can bind to
...
Other receptors are CXCR4 or CCR5 to which the viral receptor gp41 binds
...
Tight attachment of virus to host surface receptors leads to membrane fusion
...
HIV RNA contains 3 key enzymes – reverse transcriptase, integrase, and
protease
...

Key target sites for antiviral therapy: Fusion inhibition, inhibition of reverse transcriptase, inhibition of DNA integration, interference
with protein manipulation, and interference with capsid maturation
...
Fusion inhibitors = Enfuvirtide
...
There are
two receptors on HIV – gp120 and gp41 bind to host cell receptors like CD4 and either CCR5 or CXCR4 which are chemokine coreceptors found on CD4+ T-helper cells
...
Gp41 is responsible for fusion of cellular and viral membranes
...
Gp41 and gp120 are cleaved from the trimer gp160
...
Resistance can occur in the binding area
of gp41
...
Most common side effects= injection site reaction after
subcutaneous injection
...
Maraviroc is another example
of fusion inhibitors; it works by binding to CCR5 co-receptor preventing interaction with gp120
...
Inhibition of reverse transcriptase using Anti-HIV nucleoside analogue reverse transcriptase inhibitors
...
These drugs become incorporated into
the growing DNA chain and terminate elongation
...
Zidovudine is a
thymidine analogue where the 3-OH group is replaced by an azido group (N3)
...
AZT is converted to a zidovudine triphosphate by
cellular enzymes in infected and non-infected cells
...
Zidovudine side effects =
dyspepsia, diarrhoea, headache, vomiting and anaemia
...

Stavudine is slightly less active than zidovudine and there is a risk of peripheral neuropathy
...
EFZ does NOT compete with nucleoside reverse transcriptase inhibitors
...
In HIV infected patients the time to peak plasma concentrations are
reached in 3-5 hours and steady state plasma concentration are achieved in 6-10 days
...
Efavirenz cannot be given to pregnant women as it is teratogenic
...

3
...
Reverse
transcriptase converts viral ssRNA into dsDNA
...
The PIC then enters the nucleus and binds to the host cell DNA
...
Subsequent integration of HIV cDNA
(complementary DNA) into the host involves viral integrase
...
Integrase inhibitors –
inhibit viral integrase and prevent DNA integration so the viral DNA will be circularised by host enzymes and degraded
...
Insertion of viral DNA
into the host genome is called strand transfer
...

Raltegravir does NOT result in increased serum levels of total cholesterol, LDL cholesterol or triglycerides
...
Raltegravir exhibits potent anti-retroviral activity when used with other HIV therapies
...
Interference with protein modification by HIV protease inhibitors
...
To become
functional, the individual proteins MUST first be excised from the longer polypeptide chain (1)
...
Budded immature viral particles that contain catalytically inactive protease cannot undergo maturation to an infective form
...
The two asparagine residues at position 25 in each subunit (1) are essential catalytic residues that activate a water molecule
to hydrolytically cleave the polyprotein that binds between the two subunits (1)
...

Since the viral protease activity was shown to be essential to infection (1) there was an interest in protease as a potential target of new
antivirals
...
They function by binding in the tunnel/cleft between protease
subunits (1) preventing correct interaction with substrates (1)
...
The function of
protease inhibitors is to prevent post-translational modification of viral proteins leading to the production of non-infectious virus
particles (1)
...
So they are very effective in combination with other drugs (1)
...
Side effects = lipodystrophy (1) which is
abnormal distribution of body fat (characterised by peripheral lipoatrophy, fat accumulation within the abdomen, hyperlipidaemia
and insulin resistance (1)), high blood sugar and development of diabetes, liver toxicity, blood tests that monitor liver function as well
as cholesterol and triglyceride levels are routine in patients on protease inhibitor therapy (1), high sugar/cholesterol is typical of
protease inhibitors (1)
...
Some protease
inhibitors can be used against hepatitis C (1)
...

Interference with capsid maturation using maturation inhibitors
...
Maturation of HIV-1 particles, which occurs as they bud off from
the infected cell, is triggered by the step-wise cleavage of the major viral structural polyprotein Pr55Gag to individual, mature Gag
proteins which form the capsid
...
Current
maturation inhibitors prevent the viral protease from processing Gag at one particular cleavage site
...
Failures in clinical trials of bevirimat occur due to polymorphisms in putative capsid protein cleavage sites
preventing drug binding
...

Treatment of other viral infection considerations: 1
...
It determines how safe or toxic a drug is
...
Severity of disease
...
It replaces thymidine in growing
DNA chains, and can still form chains as it possesses –OH groups at 5 and 3 positions on sugar
...
It is too toxic to be used systemically, it cannot kill latent viruses and it only prevents
replication
...
Aciclovir (Zovirax) is a substituted guanine derivative
...
Aciclovire is inactive and must be phosphorylated to
form the nucleoside triphosphate in order to be used by DNA polymerase
...
Nucleoside
isolated from a Caribbean sponge – cryptotethya crypta are the basis for synthesis of acyclovir
...

Activation of acyclovir: In the virus–infected cells aciclovir is phosphorylated by the viral enzyme thymidine kinase to form aciclovir
monophosphate
...
In non-infected cells
thymidine kinase does NOT exist and so aciclovir is not phosphorylated and remains inactive
...
Aciclovir can be given orally, topically or IV infusion
...
pH of aciclovir solution is high (pH 11) and may lead to irritation at the site
of infusion and because it is very insoluble absorption by mouth is poor and so high doses need to be administered
...
Famiclovir is also an oral prodrug which is converted by
first pass metabolism to the antiviral drug penciclovir
...
Penciclovir triphosphate inhibits DNA polymerase of
viruses but has no effect on cellular DNA polymerase
...
Development of resistance: the virus may become thymidine kinase negative and so the drug will not
become inactivated, the thymidine kinase may be altered in such a way that it does NOT activate aciclovir, the viral DNA polymerase
may be altered so that it does not recognise the aciclovir triphosphate
...

Nucleoside analogue-3: Ganciclovir is a nucleoside analogue of guanosine
...
The di- and tri- phosphates are produced by the actions of cellular enzymes
...
Ganciclovir mode of action: ganciclovir triphosphate slows viral DNA replication however, short subgenomic



CMV DNA fragments continue to be produced
...
Side effects: combination of high intracellular
levels of ganciclovir triphosphate and slow breakdown and elimination from infected cells means ganciclovir is MORE toxic than
aciclovir, leucopenia – abnormal diminution of white blood cells, thrombocytopenia – abnormal diminution of platelets, rash, CNS
problems, teratogenicity, impairment of fertility, mutagenicity and potential carcinogenicity
...

Ganciclovir is highly active against all herpes viruses and does NOT eradicate the virus
...
Used for patient with life-threatening cytomegalovirus infections, usually these patients are immunocompromised
...
Vidabarine is a nucleoside
purine analogue developed in the 1960’s
...
It is active
against all herpes viruses
...
Vidabarine has the same activity against TK-HSV strains which are resistant to aciclovir
...
Incorporation of ara-ATP into viral DNA
causes a decrease in the rate of primer elongation and chain termination
...
This prevents reduction of nucleoside disphosphates to their
deoxyforms reducing the available dATP pool, thereby reducing viral replication
...
Viral strains resistant to vidabarine show changes in DNA polymerase
...
Foscarnet is a non-nucleoside phosphonic acid derivative with activity against herpes viruses
...
It does NOT require intracellular activation and appears to inactivate DNA polymerase directly by blocking
pyrophosphate binding site to block the binding of the pyrophosphate moiety that is cleared from a dNTP during DNA synthesis
...
It is orally bioavailable and IV administration is required
...

Influenza viruses A and B are antigenically unstable
...
Influenza vaccines have been available since late 1960’s
...
Viruses are grown in chick embryos and are chemically inactivated and purified
...

Oseltamivir and Zanamivir inhibit the neuraminidase enzyme on the viral envelope
...
The enzyme hydrolyses the sialic acid end of glycoproteins and glycolipids present of the surface of host cell membranes
...
Side effects: Oseltamivir
= nausea, vomiting, diarrhoea, abdominal pain, headache, hepatitis and elevated liver enzymes, and rash
...
There are no other toxic effects as the drug is NOT systemic

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