Lecture Notes - Agents of Infectious Diseases - Biomedical Sciences - University of Warwick
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Biomedical Sciences
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The University Of Warwick (UoW)
These comprehensive "Agent of Infectious Disease" notes provide a detailed exploration of various topics related to infectious diseases. The notes cover essential aspects such as viral replication, classification, major epidemics, and pandemics. The study material delves into the epidemiology of in...
Lecture 10
o Adaptive immune system takes about 7-10 days which is too slow. We
therefore rely on our innate immune system for protection in the first
few critical hours or days after pathogen challenge.
o Three lines of innate immune system defence:
1. Barriers: physical and chemical
-Thick layer of keratinised dead cells – skin.
-Tight junctions between epithelial cells.
-Acidic stomach pH
-Mucus layers.
2. Cell-intrinsic responses
-Pathogen-induced phagocytosis
-Degradation of dsRNA
3. Specialised proteins and specialised cells
-Professional phagocytes – neutrophils, macrophages
-NK (natural killer) cells
-The complement system
o Innate immune responses are NOT specific to particular pathogens
unlike the adaptive immune responses which are.
o Mucus layers – skin and other epithelial surfaces lining respiratory,
intestinal, and urinary tracts provide a physical barrier.
o In addition, a mucus layer on moist epithelial surfaces protects against
microbial, mechanical, and chemical insults.
o Fish and many amphibians also produce a mucus layer on the skin.
o Example: Hagfish (slime eel) eel-shaped jawless marine animals with a
skull but no vertebral column.
o The mucus layer is made from secreted mucins and other
glycoproteins.
o It is slippery: hard for pathogens to attach to mucus-coated epithelia.
o In many cases, epithelial cells have beating cilia, which can facilitate
clearance of pathogens.
o Structure of mucin: cytoplasmic domain and a transmembrane domain,
core protein, and O-linked sugars which form long branched chains.
The largest component of the molecular weight of a mucin is the
sugars.
o These sugars are highly soluble, so they hold onto water which means
mucin is a slippery molecule.
o Mucus layer also contains defensins: small (12-15 amino acids in
length) positively charged antimicrobial peptides, which have
hydrophobic or amphipathic helical domains (where the positive
, charges lie on one face of a coil, and hydrophobic residues lie along
another).
o Ancient defences: found in all animals and plants.
o Defensins have wide-antimicrobial activity and can kill or inactivate:
-Gram-positive and gram-negative bacteria.
-Fungi, including yeasts
-Parasites, including protozoa and nematodes
-And enveloped viruses such as HIV
o There are multiple defensins, grouped into multiple classes, so there is
a wide repertoire of targets.
o Example: Alpha-defensins inhibit infection by HPV: beta-defensins are
less efficient.
o How do defensins kill? The mechanism remains somewhat uncertain.
Their hydrophobic domains or amphipathic helices may enter into the
core of the lipid membrane of the pathogen and destabilise it, leading
to cell lysis.
o Following membrane disruption, the positive charges may interact with
negatively charged nucleic acids in the pathogen.
o How do defensins lyse pathogens, but not our own epithelial surfaces?
They are much more active on membranes that do not contain
cholesterol (our membranes contain cholesterol).
o Relatively non-specific action and so it is difficult for pathogens to
acquire resistance.
o Pathogen-associated molecular patterns (PAMPs): pathogens do
occasionally breach the epithelial barriers.
o How does the innate immune system recognise them as ‘non-self’?
o The innate immune system recognises molecules (pathogen-associated
or microbe-associated immunostimulants) that are common to many
pathogens, but essentially absent in the host.
o An alternative name is PAMPs, referring to an older view that the
innate immune system recognises ‘patterns’ in pathogens.
o Various classes of PAMPs are recognised by human cells:
1. N-formylmethionine (fMet) is used for bacterial translation
initiation. Proteins containing fMet also attract neutrophils.
2. Peptidoglycans from bacterial cell walls.
3. Bacterial flagellae.
4. LPS from gram-negative bacteria
5. Mannans, glucans, and chitin from fungi.
6. ‘CpG’ (C phosphate G) motifs in bacterial or viral DNA.
o Pattern recognition receptors: PAMPs are recognised by soluble
receptors in the blood by cellular receptors.
o PAMPs (peptidoglycans, mannans, glucans, and chitin) are recognised
by components of the complement system (blood receptors) and they
perform direct killing and aid in phagocytosis.
,o PAMPs (LPS, CpG motifs, and flagella) are recognised by toll-like
receptors (membrane-bound) and they are essentially an alarm
system.
o Complement activation targets pathogens for lysis – complement:
about 20 soluble proteins that are activated sequentially upon
infection.
o Lectin pathway: mannose and fucose binding proteins.
1. The early complement components are proenzymes that activate
the next member in line by cleavage, resulting in an amplified
proteolytic cascade.
2. The pivotal proteolysis is the one that cleaves C3 into C3a and C3b.
3. C3a: calls for help. Attracts phagocytes and lymphocytes,
stimulating inflammation.
4. C3b: binds covalently to the pathogen’s plasma membrane.
5. Pathogen-bound C3b stimulates a local cascade of reaction (C5-C8)
at the marked membrane.
6. C9 is inserted into the membrane.
7. A C9 pore breaches the membrane, C9 multimers form a
membrane-attack complex.
8. Pathogen lysis.
o There are amplifier proteolytic cleavage pathways that lead to the
direct activation of C3 from two different recognitions of pathogens.
o Toll-like receptors: Toll is a Drosophila transmembrane protein with a
large extracellular domain with repeating motifs (leucine-rich repeats)
that are versatile binding motifs for a variety of proteins.
o Binding to pathogenic fungi sends a signal to the nucleus that results
in the upregulation of the expression of antifungal defensins.
o Toll-like receptors have the same overall structure- and do very similar
jobs.
o Most TLRs are on the cell membrane of epithelial cells and
macrophages, dendritic cells and neutrophils.
o TLRs bind PAMPs (an alarm system)
o TLR4; LPS
o TLR5; flagellum
o TLR9; CpG motifs in DNA
o Signals to the nucleus follow this binding, resulting in transcription of
hundreds of genes, especially those that promote inflammation.
o Defensins and TLRs are ancient immune system components. Proteins
related to TLRs and defensins are apparently involved in innate
immunity in all multicellular organisms.
o In plants, for example, membrane receptors with leucine rich repeats
and domains homologous to the cytosolic domains of TLRs are
required for resistance to fungal, viral and bacterial pathogens.
, o This suggests that defensins and TLRs pre-date the ancestral split
between animals, fungi and plants, estimated at 1576 +/- 88 million
years ago.
o Evasion of the innate immune system: Neisseria gonorrhoea. Galen,
second century, the first usage of the term ‘gonorrhoea’, implied of
‘flow of seed’.
o For centuries after, gonorrhoea and syphilis were confused (the two
diseases were often present together in infected individuals).
o Paracelsus (1530) thought that gonorrhoea was an early symptom of
syphilis
o The confusion was further heightened in 1767:
-Scottish physician John Hunter intentionally inoculated himself with
pus from a patient with symptoms of gonorrhoea and gave himself
syphilis. He championed its treatment with mercury and cauterization.
Published 1786.
o He claimed it proved his point that Paracelsus was correct.
o 1879: the causative agent of gonorrhoea, Neisseria gonorrhoea, was
first described by A. Neisser.
o 1885: the organism was grown in pure culture (requires nutrient
supplementation to grow in laboratory cultures: specifically, it requires
chocolate agar.
o Its relationship to human disease was later established using human
volunteers.
o Because innate immune system cells are migratory, gonorrhoea can
sometimes spread throughout the body and cause other diseases.
o Gonorrhoea: symptoms. ~10% of infected males and ~80% of infected
females are asymptomatic.
o Infection of the genitals can result in purulent foul-smelling discharge,
and via inflammation, dysuria (painful urination) and urethritis,
pharyngitis (inflammation of the pharynx) and proctitis (inflammation
of the anus).
o In addition: Males: prostatitis and or orchitis
o Females: Pelvis inflammatory disease, which can result in infertility in
10 ~20% cases.
o Neonates: conjunctivitis in newborns exposed to Neisseria gonorrhoea
in the birth canal can lead to corneal scarring and blindness.
o Disseminated Neisseria gonorrhoea infections can occur, resulting in
endocarditis and meningitis.
o Prevalence: 2010 target of 19 cases per 100,000 people. In the UK,
Neisseria gonorrhoea is the second most common bacterial STI.
o Transmission rates: A female with an infected man has a ~50%
chance of infection
o A male with an infected woman has a ~20% chance of infection.
o The capsule of Neisseria gonorrhoea lacks LPS, instead it contains LOS
(lipooligosaccharide) which has fewer sugars and therefore holes.
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