Immune Evasion by Microbes Flashcards
What are the 2 groups of diseases causes by S. Aureus?
- Localised pyogenic or “pus-producing” diseases that are characterised by tissue destruction by hydrolytic enzymes and cytotoxins
- diseases mediated by toxins that function as super antigens producing systemic diseases
What are properties of S. Aureus?
Can grown aerobically and anaerobically over wide range of temps. and in high conc. of salts
Has catalase which protects S. Aureus from peroxides produced by neutrophils and macrophages
Has coagulase which converts fibrinogen to insoluble fibrin that forms clots and can protect S. Aureus from phagocytosis
How is S. Aureus structures?
Has a polysaccharide capsule that protects bacteria from phagocytosis
Has cell surface proteins (Protein A, clumping factor proteins) that mediate adherence of the bacteria to host tissues
What hydrolytic enzymes and cytotoxins does S. Aureus have?
Lipases, nucleases and hyaluronidase that causes tissue destruction
Cytotoxins: alpha, beta, delta, gamma, leukocidin
They lyse erythrocytes, neutrophils, macrophages and other host cells
What toxins does S. Aureus have and what are their properties?
Enterotoxins: heat stable and acid- resistant toxins responsible for food poisoning
Endofoliative toxins A and B that cause superficial layers of skin to peel off (scaled skin syndrome)
Toxic shock syndrome toxin: heat and protease resistant toxin that mediates multi organ pathology
Where is S. Aureus commonly present?
Common cause of infection in community and hospitals because bacteria is easily spread
Antibiotic resistant strains (e.g. MRSA) are widely distributed in both hospitals (HA- MRSA) and community (CA-MRSA)
What are examples of S.Aureus Pyogenic diseases?
Folliculitis Impetigo Furuncles (Boils) and carbuncles Wound Infections Osteomyelitis Pneumonia Endocarditis Septic Arthritis
What is Impetigo?
Localised skin infection characterised by pus filled vesicles on a reddened erythematous base
Seen mostly in children on their face and limbs
What is Folliculitis?
Impetigo involving hair follicles such as beard area
What are furuncles and carbuncles?
Large, pus filled skin nodules, can progress to deep layers of skin and spread into blood and other areas of body
What are wound infections?
Characterised by erythema and pus at site of trauma, more difficult to treat if foreign body is present
Majority of infection caused by MRSA
What is pneumonia?
Abscess formation in lungs, observed primarily in very old and young.
Frequently following viral infections of respiratory tracts
What is endocarditis?
Infection of epithelial lining of heart, disease can progress rapidly and is associated with high mortality rate
What is osteomyelitis?
Destruction of bones particular in highly vascularised areas of long bones in children
What is septic arthritis?
Infection of joint spaces characterised by swollen, reddened joint with accumulation of pus- most common cause of septic arthritis in children
What are examples of S. Aureus toxin mediated diseases?
Food poisoning- after consumption of food contaminated with heat- stable enterotoxin: diarrhoea, cramps, vomiting and cramps onset is rapid but resolves in 24hrs (no requirement for bacteria to multiply)
Scalded skin syndrome- bacteria in localised infection produces toxin that spread to blood and causes outer skin layer to peel off- seen almost exclusively in very young children
Toxic Shock Syndrome: bacteria produce toxin that effects many organs: fever, hypotension, diffuse, macular erythematous rash
How is S. Aureus treated and prevented?
Localised infection managed by incision and drainage
Antibiotics for infection
Oral therapy includes trimethoprim- sulphamethoxazole , clindamycin or doxycycline
Vancomycin used for IV therapy
Cleaning of wounds and use of disinfectant
Thorough hand washing and covering exposed skin
Medications for food poisoning is symptomatic- source infection should be found to protect others
No vaccine available
What are common factors found in bacteria?
LPS in gram-negative bacteria
LTA in gram-positive bacteria
These are often detected by our immune response
What are neutrophils?
Most abundant leukocytes
Recruited to areas of infection
Detect microbes
Perform effector functions- kill microbes
Neutrophil responses must be balanced to prevent infection and damage in host
What do neutrophils do?
Adhesion
Priming
Chemotaxis- migrate along the gradient of C3a and C5a and bacterial proteins towards compliment components and bacteria proteins
Activation:
-phagocytosis
-opsonisation (antibodies and compliment)
-Inflammation (Recruit other immune cells)
-degranulations (release of reactive O2 species, antimicrobial molecules)
-Transmigration (recruitment of neutrophils- C5a and C3a bind C3aR and C5aR, endothelial cells express ICAM, neutrophils roll along the surface)
What is staphylococcus Aureus?
Gram-positive bacteria that is commensal and lives harmlessly in 30% of humans
It avoids immune response by releasing super antigens which interfere with T cell function and lekocidins which lead directly to cell death
What is antibody opsonisation?
Antibodies bind bacteria allowing:
- deposition of compliment in classical complement pathway
2 neutrophils and other phagocytes the ability to detect microbes
How does S. Aureus evade opsonisation?
Expresses capsule on its surface
This helps hide antigenic structures that can be detected by innate and adaptive immune components, including compliment and antibody
What are other bacteria which express capsule?
E. coli (80 types) S. pyogenes Pseudomonas aueroginosa S. pneumonia (91 capsule types) S. agalactiae (9 capsule types
How does S. Aureus use protein A to avoid opsonisation?
Spa surface protein (codes protein A) binds antibodies via their Fc regions instead of their Fab regions
This prevents opsonisation and therefor neutrophils can’t detect S Aures
What other bacteria express surface proteins that bind antibodies?
Streptococcus dysgalactiae (Protein G binds IgG) Peptostreptococcus Magnus (Protein L binds IgG) Streptococcus agalactiae (Beta protein binds IgA)
How does S. Aureus evade detection by biding to IgG?
S. aureus SSL10 binds to Fc region on IgG
It prevents Fc receptors on neutrophils detecting IgG on surface of S. Aureus
In summary how does S. Aureus evade antibody detection?
Capsule expression
Inhibit antibody opsonisation
Inhibit detection of antibody
What are other antibody evasion strategies?
- Protases cleave antibodies- group B streptococcus, porphyromonas gingivitis, streptococcus pyogenes, Neisseria gonorrhoea, haemophilia influenzae
- Antigenic Variation- surface structure can be switched to another surface structure- N. gonorrhoea (Opa and LOS antigens) , s. pneumonia (Cap)
What is compliment opsonisation?
Compliment system is composed of a large number of proteins that react with one another to opsonise pathogens or directly kill them by membrane attack complex (MAC) formation
What are key steps of the compliment cascade?
- Initiation
- Formation of C3 convertase
- Formation of C5 convertase
- MAC formation
What are the 3 pathways to activate compliment?
- Classical
- MBL/ Lectin
- Alternative (not dependent on antibodies)
All 3 pathways will lead to formation of C3 convertase which will lead to the compliment cascade resulting in formation of MAC
What happens in the classical pathway?
Antibodies bind to antigens
This results in complex C1QRS being formed
This can activate C3 convertase (C4BC2B)
What happens in the lectin/ MBL pathway?
MBL detects and binds to carbohydrates or sugars on surface of microbes and forms complex with MASP
This results in generation of C3 converstase (C4BC2B)
What happens in the alternate pathway?
C3b is sporadically deposited onto the surface of microbe
Recruitment of factor B results in the formation of C3 convertase C3bBb
What is C3b?
C3b can be detected by compliment receptors expressed in neutrophils and other phagocytes
Upon its detection it results in phagocytosis of microbes
How is C5 convertase formed?
Both C3 convertases (C4bC2b and C3b8b) act to produce more C3b when factor b and C3b work together
This results in formation of C5 convertase C3bBb3b
This C5 convertase is able to degrade C5 into C5a and C5b
How is the MAC formed?
If C5b is deposited onto microbial surface its able to recruit C6, C7 and C9 which forms MAC
How does S. Aureus evade compliment opsonisation?
- S. aureus SCIN binds C3bBb and inhibits convertase
2. S. Aureus Efb binds C3d and inhibits factor B binding C3
How does S. Aureus evade compliment opsonisation by SCIN?
SCIN protein binds C3bBb and inhibits formation of C3 convertase and C5 convertase
This prevents
- C3b deposition- phagocytes unable to detect C3b opsonised microbes
- C3a formation- lower chemoattract signals for recruitment of immune cells
- C5a formation- less C5a deposited onto surface so less MACs formed
How does S. Aureus evade compliment opsonisation by binding C3d?
S. Aures Efb (E factor b) protein binds to C3d in C3 which induces conformational change
This prevents:
-binding of factor b to C3
-C3dg binding CR2
What other complement evasion strategies are used?
- Degrade compliment components- proteases cleave C3 or C5 into non-functional forms
- Recruit host-derived regulators- C3b inactivated by fH on bacterial surface, C4BP degrades C2a from C3 convertase (C4bC2b)
How do neutrophils sense and respond to their environment?
Neutrophils express hundreds of different immune receptors at their surface or in their secreting vesicles (SVs) and granules
Immune receptors allow neutrophils to sense and respond to their environment- they detect microbes, microbial products or self proteins
How do immune receptors detect bacteria?
Pathogen recognition receptors PRRs directly detect microbes or microbial products. Causes neutrophils to be primed or activated
What are the different immune receptors and what do they detect?
TLR receptor- detect conserved microbial structures
CLEC receptor- detect microbial carbohydrates
FPR receptor- detect formulated peptides
How do immune receptors indirectly detect bacteria?
Microbes can become opsonised by antibodies and compliment
Neutrophils detect opsonised microbes through Fc receptor or compliment receptor
How do immune receptors modulate function?
Activatory receptors: enhance immune cell activity
Inhibitory receptors: suppress immune cell activity- have inhibitory motifs in their cytoplasmic tracts and counteract ITAM motifs found in activatory receptors e.g. Fc receptors
How does S. Aureus evade neutrophil detection?
S. aureus inhibits chemotaxis
Chemotactic receptors:
- C5aR detects C5a
-FPR1 detects formulated peptides (fMLP)
S. Aureus inhibits these chemotactic receptors:
-CHIPs bind C5aR and FPR1 and prevents binding of their agonists (C5a and formulated peptides)
This means neutrophils do not migrate to sites of infection and do not become activated through C5aR or FPR1
How does S. Aureus prevent phagocytosis?
S. Aureus FLIPr and SSL5 block FC receptors
FLIPr inhibits Fc gamma receptors - prevents detection of IgG-opsonised bacteria
SSL5 inhibits Fc alpha receptors (IgA)
This reduces antibody mediated phagocytosis
How does S. Aureus kill neutrophils?
S. Aures can express a number of different toxins that can bind to neutrophil receptors- binding causes their lysis
S. Aureus can also bind to activating receptor and blocks their fucntion
What other forms does S. Aureus use to suppress neutrophil responses?
Bind inhibitory receptors
Inhibit effects of antimicrobials
Manipulate intracellular signalling
Modify bacteria surface
