Lecture 14: Host Immune defences Flashcards
What is secretory IgA?
One of the antibody produced by the immune system
Where does Secretory IgA act on?
Gut lumen
IgG
Certain bacteria can tag at IgG and prevent action
What are Anti-microbial peptide?
Essential component of the host defence against infection Part of the innate defence Small proteins (12 to 80 amino acids) produced in humans by epithelial cells (paneth cells) and immune cells (neutrophils,macrophages) Broad spectrum microbial activity
What does Anti-Microbrial peptide act on?
Lots of bacteria and viruses
What are the main types of AMP?
Alpha and beta defensins and Cathelicidins
How do AMP act?
Binding to microbial membrane and creating pore-like structure leading to microbes killing
How does AMP cause damage to the membrane?
All AMPS bind on the membrane of bacteria and create pore
What are the bacterial resistance to AMP?
Modification of AMP target Production of molecules preventing binding of AMP Production of proteolytic factors degrading AMP Removal of AMP from
Membrane or cytoplasm (efflux pumps)
What are gram positive membrane made of?
Phospholipid bilayer, peptidoglycan
What charge does bacterial membrane have?
They are negatively charged which attract AMP because they are positively charged
How do you modify the surface membrane of bacteria to avoid AmP binding to membrane?
Modifying teichoic acid or phospholipid bilayer by integrating positively charged amino acids of neutral charge so they reduce the negative charge
What are the two phospholipid bilayer of gram negative bacteria?
Periplasm and peptidoglycan
What are two examples of bacteria modifying membrane to reduce targeting by AMP?
Salmonella: addition of a sugar/ monoamine on LPS E.coli: lipid A of LPD could be modified by acetylation
How does gram-positive bacteria (staph. Aureus) resist AMP?
Techoid acid modification Phospholipid modification - increase positive charge
How does gram- negative bacteria such as salmonella resist AMP?
Modify LPS molecules with aminoarabinose Acetylation of lipid A unit of LPS molecules (Yersinia enterocolitica, E.coli)
How do you know avoid binding of AMP?
Change charge of bacteria
What do a lot of bacteria produce?
Capsule
What is the role of capsule?
Formed from polysaccharide and puts a protective coat around bacteria
What is the consequence of of producing capsule?
The charge on bacteria changes and AMP can’t bind
What do some bacteria produce?
Pilus
What can pilus bind to?
AMP
What does pilus do?
Prevent AMP from reaching the membrane of bacteria
What is example of polysaccharide capsule?
Klebsiella pneumoniae Neisseria meningitidis
What are examples of pilus?
PilB in group B Streptococcus
What is one way bacteria can become resistant to antibiotics?
Efflux pumps
What are examples of proteolytic factors?
Pseudomonas aeruginosa elastase degrades LL-37 Proteus mirabilis ZapA metalloproteass degrade AMPs
What are examples of efflux pumps?
Neisseria spp - the energy-dependent Met efflux pumps mediate resistance to AmP S.Typhimuri AMPs are exported by sap efflux system
What is sap sensitive to?
Antimicrobial peptides
What is the first innate immune defence at mucosal surface?
Secretory IgA immunoglobulins
What is key role of secretory IgA?
Immune homeostasis
What is immune exclusion?
Secretory IgA neutralise microbes and toxin, prevent them to reach equilibrium
How does secretory IGA faciliate Immune exclusion?
Agglutination Entrapment In mucus Facilitating clearance via peristalsis
What do plasma cells secrete?
IgA directly in the lumen of the gut
What does IgA within mucus and gut do?
Bind directly to bacteria and prevent them to reach the epithelium
What are some examples of IgA proteases?
Serine-endopeptidase zinc metalloprotease
What do serine-endopeptidase or zinc metalloprotease cleave?
Specific peptide bonds in IgA proline hinge region
What do gram-positive organisms produce and secrete?
IgA protease dedicated to cleave and disable IgA
What are 3 main pathogenic bacteria producing IgA proteases?
Streptococcus pneumoniae Haemophilus Influenzae Neisseria meningitidis
What is complement?
Part of first response of innate immune system
What is complement?
Group of soluble proteins of bloodstream; Proteolytic system with more than 30 proteins Circulate in inactive form Activated by pathogen detection Chain reaction, activated proteins activate other complement proteins by cleavage
What are the 3 main functions of complement?
Opsonisation (c3b) MAC Enhancing inflammation (c5a)
What is opsonisation?
Specific binding by protein of immune system Once opsonised they are easily recognised by phagocytes and degraded Key element: C3b Pathogen clearance by phagocytes
What is MAC?
Main element is c5b Membrane attack complex and direct lysis of pathogens Bind at the surface of bacteria and create a pore
What is enhancing inflammation?
Main element is c5a and c3a Activation and recruitment of phagocytic cells by anaphylatoxins Released by digestion of complement components
What are the 3 main pathways of activation of complement?
Classical pathway Lectin pathway Alternative pathway
What is classical pathway?
Activated when bacteria are recognised by antibodies Antibodies will bind at surface of bacteria IgM/IgG Constant portion of the antibody will be recognised as a first molecule of the complement [C12] There will then be antigen/antibody complex
What is the lectin pathway?
Specific proteins that recognise sugar residues at surface of bacteria Mannose binding lectin protein will attract molecules of the complement
What is the alternative pathway?
Activation takes place at the surface of bacteria directly via one of the molecule of complement
What cleavage occurs when complement is activated by either classical or lectin pathway?
C4 and C2 molecule of the complement which give rise to C4a, C4b, C2a and C2b
Where do C4a and C2b bind?
Surface of bacteria and called c3 convertase
What do the alternative pathway of c3b bind?
Surface of bacteria and it will bind to another factor Bb and factor Aa
What do c3bBb form?
C3 convertase
What is C3b involved in?
Opsonisation and phagocytosis
When c3b associate with c3 convertase (C4b2b) form?
C5 convertase
Wha is c5 convertase?
Complex of protein that activate and convert c5 into c5b and c5a
What forms the membrane attack complex?
C5b puts other molecule of complement (c6-c9)
What happens when there is pore in the bacterial membrane?
Influx of water in bacteria Lysis of bacteria
What does c5a and c53e induce?
Chemotaxis of immune cells inflammation and will act on vasculature and degradation of muscle cells
What is the main controller of the complement system?
Inhibitor of C4BP - attack’s at level of c3 convertase (c4b2b) - inhibits system inhibitor factor H (FH) - inhibits c3b but also acts on c3 convertase from alternative pathway
What are the 4 main strategies of resistance to complement?
Resistance to complement detection by steric hindrance via expression of polysaccharide capsule Resistance to complement via recruitment or mimicking of complement regulators (complement FH and C4BP) Resistance to complement via enzymatic degradation of complement proteins Resistance to modulation via modulation or inhibition of complement proteins
What are the major virulence factors that limit dessication, block infection by bacteriophages and limit host immune defence?
Bacterial capsular polysaccharides
What do the major virulence factors resist access to?
Cell surface antigens
What do some capsules contain?
Hyaluronic acid - prevalent in human tissue and is one main component of connective tissue
What is the consequence of hyaluronic acid?
Bacteria will become less detected by immune system
What is streptococcus pyogenes?
Hyaluronic acid similar to glycosaminogylcans abundant in human
What is group B streptococcus (GBS)?
Sialic acid mimic human common glycoepitopes of mammalian cells - integrated in capsule of different bacteria and reduce detection by immune system
What do capsules do?
Cover and mask bacterial antigens and prevent complement deposition/activation at bacterial surface: prevent opsonised phagocytosis
What is main role of M proteins?
Avoid detection and phagocytosis
What does staph.aureus secrete?
Proteins that act as a complement inhibitor (inhibit convertases)
What does the staphylococcal complement inhibitors (SCINs) inhibit?
C3 convertase blocking the 3 alternative complement pathways
What does extracellular fibrinogen-binding protein and extracellular complement binding proteins bind and inhibit?
Bind c3 and inhibit C3 and C5 convertases; inhibit opsonisation and phagocytosis
What is an example of enzymatic degradation of complement proteins?
C5a peptides from Streptococcus spp directly targets and degraded C5a anaphylatoxins and prevents phagocytes chemotaxis
What is the summary of C5a action?
- Neutrophil Activation 2. neutrophil Adhesion 3. Neutrophil emigration and chemotaxis 4. Monocyte Activation Mast Cell degradation —> smooth muscle contraction and increased vascular permeability
What is the effect of C5a?
Inflammation and elimination targeting of pathogen
What does staphylococcal protein A (SPA) bind to and prevent?
Bind to Fc portion of IgG and prevent opsonisation and phagocytosis
What does SPA recruit?
IgG and coat bacterial surface via binding to Fc region - no opsonisation
What does chemotaxis inhibitory protein of S.aureus (CHIPS) bind to and antagonise?
C5a receptor and prevents neutrophils and monocytes response to C5a
What does strep pyogenes produce?
cysteine protease, ides
What does Ides stand for?
Immunoglobulin G-degrading enzymes
What does ides cleave?
IgG
What happens during degradation of IgG?
Cleave hinge region separating Fc fragment from Fab Protection from antibody-degrading enzyme, complement deposition, phagocytosis
What does Enteropathogenic (EPEC) cause?
Infantile diarrhoea in the developing world
What does Enterohaemorrhagic (EHEC) cause?
Severe illness in developed countries Acute gastroenteritis and Haemolytic Uremic syndrome Production of Shigatoxin - kidney failure
What is attaching and effacing lesions?
Microvilli are completely destroyed and bacteria attaches to the cell
What is pathogenic island?
Gene clustered on one part of the genome
What is LEE?
Locus enterocyte effacement
What does molecule of syringe do?
Connect the cytoplasm of the bacteria to the cytoplasm of the target cell
What does bacteria use to directly inject protein into cell?
Syringe
What was the first protein injected inside cytoplasm of cytoplasm called?
Tir
What is the function of Tir?
Serves as a receptor and sits at the intact phase between off cell and bacteria
What are the two main pathways of Phagocytosis?
Osponin dependent phagocytosis Osponin- independent phagocytosis
What does opsonisation dependent pathway depend on?
Complement protein —> C3 part or the IgG
When bacteria is recognised by opsonisation complement or IgG it is said to be opsonised, why?
It’s a way for the immune system to efficiently phagocytise the pathogenic microbe
What recognised the bacteria that has been opsonised?
Complement receptor on the surface of macrophages and will undergo phagocytosis
What recognised bacteria that has been opsonised by IgG?
Fc receptor and it will ingest and phagocyte the bacteria
What prevents the opsonised independent phagocytosis?
EPEC?
