Immune Evasion Flashcards
The two groups into which diseases caused by body weight are divided into
- localized pyogenic or “pus-producing” diseases that are characterized by tissue destruction mediated by hydrolytic enzymes and cytotoxins
- diseases mediated by toxins that function as superantigens producing systemic diseases.
Properties of S.Aureas
• Ability to grow aerobically and anaerobically, over a wide range of temperatures, and in the presence of a high concentration of salt; the latter is important because these bacteria are a common cause of food poisoning
• Polysaccharidecapsulethat protects the bacteria from phagocytosis
• Cell surface proteins (protein A, clumping factor proteins) that mediate adherence of the bacteria to host tissues
• Catalasethat protects staphylococci from peroxides produced by neutrophils and macrophages
• Coagulaseconverts fibrinogen to insoluble fibrin that forms clots and can protectS. aureusfrom phagocytosis
• Hydrolytic enzymes and cytotoxins:
o Lipases, nucleases, and hyaluronidase that causes tissue destruction
o Cytotoxins (alpha, beta, delta, gamma, leukocidin) that lyse erythrocytes, neutrophils, macrophages, and other host cells
Toxins produced by S.Aureus and the effects
Enterotoxins(many antigenically distinct) are the heat-stable and acid-resistant toxins responsible for food poisoning
oExfoliative toxinsA and B cause the superficial layers of skin to peel off (scalded skin syndrome)
o Toxic shock syndrome toxinis a heat- and protease-resistant toxin that mediates multiorgan pathology
Epidemiology of S.Aureas
- Common cause of infections both in the community and in the hospital because the bacteria are easily spread person-to-person and through direct contact or exposure to contaminated bed linens, clothing, and other surfaces
- Antibiotic-resistant strains (e.g., MRSA) are widely distributed in both the hospital (HA-MRSA) and community (CA-MRSA)
S.Aureus Pyogenic Diseases
Pyogenic = pus producing
oImpetigo: localized skin infection characterized by pus-filled vesicles on a reddened or erythematous base; seen mostly in children on their face and limbs
oFolliculitis: impetigo involving hair follicles, such as the beard area
oFuruncles (boils) and carbuncles: large, pus-filled skin nodules; can progress to deeper layers of the skin and spread into the blood and other areas of the body
oWound infections: characterized by erythema and pus at the site of trauma or surgery; more difficult to treat if a foreign body is present (e.g., splinter, surgical suture); majority of infections both in the community and hospital are caused by MRSA; recurrent bouts of infections are common
oPneumonia: abscess formation in the lungs; observed primarily in the very young and old and frequently following viral infections of the respiratory tract
oEndocarditis: infection of the endothelial lining of the heart; disease can progress rapidly and is associated with high mortality rate
oOsteomyelitis: destruction of bones, particularly the highly vascularized areas of long bones in children
oSeptic arthritis—infection of joint spaces characterized by a swollen, reddened joint with accumulation of pus; the most common cause of septic arthritis in children
S.Aureas toxin mediated food poisoning
Food poisoning: after consumption of food contaminated with theheat-stable enterotoxin, the onset of severe vomiting, diarrhea, and stomach cramps is rapid (2 to 4 hours) but resolves within 24 hours. This is because the intoxication is caused by the preformed toxin present in the food rather than an infection where the bacteria would have to grow and produce toxin in the intestine
Scalded skin syndrome ( S.Aureus toxin mediated disease)
Scalded skin syndrome: bacteria in a localized infection produce the toxin that spreads through the blood and causes the outermost layer of the skin to blister and peel off; almost exclusively seen in very young children
Toxic shock syndrome ( S.Aureus)
: bacteria in a localized infection produce the toxin that affects multiple organs; characterized initially by fever, hypotension, and a diffuse, macular, erythematous rash. There is a very high mortality rate associated with this disease unless antibiotics are promptly administered and the local infection managed.
Treatment , prevention and control of S.Aureus
- Localized infections managed by incision and drainage
- Antibiotic therapy indicated for systemic infections; empiric therapy should include antibiotics active against MRSA
- Oral therapy can include trimethoprim-sulfamethoxazole, clindamycin, or doxycycline
- Vancomycin is the drug of choice for intravenous therapy
- Treatment is symptomatic for patients with food poisoning although the source of infection should be identified so other individuals will not be exposed
- Proper cleansing of wounds and use of disinfectant help prevent infections
- Thorough hand washing and covering exposed skin helps medical personnel prevent infection or spread to other patients
- No vaccine is currently available
What is detected in Gram negative bacteria
LPS
What is detected in gram positive bacteria
LTA
Flagella in certain bacteria
What do neutrophils do
- Adhesion
- Priming
- Chemotaxis
○ Along gradient of C3a and C5a & bacterial proteins
○ Migration towards complement components
○ Migration towards bacterial proteins - Activation
○ Phagocytosis
§ Ingestions; killing within the phagosome by antimicrobial molecules
○ Opsonisation
§ Antibodies
§ Complement
○ Inflammation
§ Recruit other immune cells
○ Degranulation
§ Release of reactive O2 species
§ Antimicrobial molecules
○ Transmigration
§ Recruitment of neutrophils
□ C5a and C3a bind C5aR and C3aR
□ Endothelial cells express ICAM
□ Neutrophils roll along surface
What do the superantigens do in staphylo aureus
interfere with T-cell function. These highly immunogenic molecules result in a massive cytokine release known as a cytokine storm which causes a high fever, nausea, fatigue, and can lead to a coma.
Staphylo Aureas and leukocidins
Directly leads to neutrophil cell death
What is anyibody opsonisation
Antibodies bind bacterial antigens, allowing
1. the deposition of complement in the classical complement pathway 2. neutrophils and other phagocytes the ability to detect invading microbes
How does the capsule help S.aureus
The capsule ( a polysaccharide) helps to hide the antigenic structures that can be detected by the innate and adaptive immune components, including complement and antibodies
Other bacteria expressing capsule
E.Coli S.Pyogenic Pseudomonas aerugonisa S.pneumonia S.aggalactiae
S.aureus protein A (SpA)
Spa surface protein binds antibodies via their Fc region not their Fab region and this prevents the normal opsonisation and therefore neutrophils cannot detect S.aureus . This prevents the complement pathway
Other bacteria that express surface proteins that bind antibodies
Streptococcus dysgalactiae ( protein G binds IgG) Pepostreptococcus Magnus ( protein L binds IgG) Streptococcus aggalactiae ( beta protein binds IgA)
SSL10 ( S.aureus)
S.aureus SSL10 binds IgG to inhibit detection . It binds to the Fc region of IgG and prevents the Fc receptors on neutrophils from detecting IgG on the surface of S.aureus . Basically prevents complement activation
3 main ways of antibody evasion of S.aureus
Capsule expression
Inhibit antibody opsonisation (Spa)
Inhibit detection of antibody ( SSL10)
Other antibody evasion strategies
Pro teases cleave antibodies
Antigenic variation
5 main ways of evading immune response
Hide antigens Disrupt function Prevent detection Degrade antibodies Modify antigenicity
Prevents or hides antibody opsonisation
What is complement opsonisation
Complement system is composed of a large number of proteins that react with one-another to opsonise pathogens or to directly kill them by membrane attack complex (MAC) formation
Key steps of complement cascade
- Initiation
- Formation of C3 convertase
- Formation of C5 convertase
- MAC formation
3 pathways to activate complement
Classical Lectin
alternative ( not dependent on antibodies)
Where are complement proteins made
produced by the liver, macrophages and monocytes. It can produce a triggered enzyme cascade system, where the activation of one enzyme leads to the activation of others.
Classical pathway triggers
Antigen- antibody complex
Left in pathway triggers
Membrane binding lectin , CRP
Alternate pathway triggers
Bacterial surfaces
Which complement pathway is used in immunosuppression
In a scenario of immunosuppression, where the body’s ability to produce antibodies is diminished, the alternative pathway can continue to fight infection, as it does not directly employ the use of antibodies.
It can be directly triggered by surface activation via the presence of bacterial endotoxins
4 major functions of complement system
lysis of infectious organisms, activation ofinflammation,opsonizationand immune clearance.
How does S.aureus evade complement opsonisation via inhibiting complement convert axes
S. aureus SCIN protein binds C3bBb and inhibits formation of C3 convertase and C5 convertase
This prevents:
C3b deposition
C3a formation
C5a formation
S.aureus inhibiting C3 processing in complement pathway
S. aureus Efb protein binds C3d in C3, which induces conformation change
This prevents
Binding of factor B to C3
C3dg binding CR2
Other bacteria release proteins binding C3:-
M. catarrhalis (UspAs)
S.aureus complement evasion
I inhibit complement convertases
Inhibit C3 processing
Inhibit MAC formation ( SSL7)
Bacterial proteins prevent C3b or MAC deposition by
Inhibit C3/C5 convertases
2) Bind complement factors and prevent their processing 3) Cleave complement factors 4) Acquire host-derived complement regulators
How do neutrophils sense and respond to the environment
Neutrophils express hundreds of different immune receptors, at their surface or in their secretory vesicles (SVs) and granules
Immune receptors allow neutrophils to sense and respond to their environment. They detect microbes, microbial products or self proteins.
Immune receptors detect bacteria vis
- Conserved microbial structures (TLR receptors)
- Microbial carbohydrates (CLEC receptors)
- Formylated peptides (FPR receptors)
If the PRRs detect microbes/microbial products => neutrophils are primed or activated
How do S.aureus CHIPS inhibit chemotaxis and activation
- CHIPs binds C5aR and FPR1 and prevents binding of their agonists (C5a and formylated peptides)
- Neutrophils do not migrate to sites of infection and do not become activated through C5aR or FPR1
How does S.aureus inhibit phagocytosis
FLIPr binds Fc g Receptors preventing the detection of IgG-opsonised bacteria
Reduces antibody mediated phagocytosis and killing of S. aureus
Additional mechanisms of neutrophil evasion
Bind and inhibit functions of activatory receptors
2) Kill neutrophils (and other immune cells) with toxins.
Ways of inhibiting neutrophil by S.aureus
) Inhibit chemotaxis
2) Inhibit detection of bacteria 3) Kill neutrophils 4) Stimulate inhibitory receptors 5) Disrupt intracellular signalling
Bacterial immune evasion
Bind inhibitory receptors; Inhibit effects of antimicrobials; Manipulate intracellular signalling; Modify bacterial surface
