Immune evasion Flashcards
Name the four mechanisms where immune evasion can occur
Opsonisation
chemotaxis
Phagocytosis
straight up murder
What are the two groups that diseases caused by S. aureus can be 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.
What are the properties of s. aureus bacteria that allow it to grow efficiently?
- Ability to grow aerobically and anaerobically, over wide range of temps
- Have a polysaccharide capsule that protects the bacteria from phagocytosis
- Cell surface proteins (protein A , clumping factor proteins) that mediate adherence of the bacteria to host tissues
- Catalase that protects staphylococci from peroxides produced by neutrophils and macrophages
- Coagulase converts fibrinogen to insoluble fibrin that forms clots to protect s. aureus from phagocytosis
What hydrolytic enzymes and cytotoxins does S. aureus produce?
Lipases, nucleases, and hyaluronidase that causes tissue destruction
Cytotoxins (alpha, beta, delta, gamma, leukocidin) that lyse erythrocytes, neutrophils, macrophages, and other host cells
What toxins does S. aureus produce and what does it cause?
Enterotoxins - many antigenically distinct that are heat and acid resistant so cause food poisoning
Exfoliative toxins A and B cause superficial layers of skin to peel off (scalded skin syndrome)
Toxic shock syndrome toxin is a heat and protease resistant toxin that mediates multiorgan pathology
List some S. aureus Pyogenic Diseases.
Impetigo : localized skin infection characterized by pus-filled vesicles on a reddened or erythematous base; seen mostly in children on their face and limbs
Folliculitis : impetigo involving hair follicles, such as the beard area
Pneumonia : abscess formation in the lungs; observed primarily in the very young and old and frequently following viral infections of the respiratory tract
Endocarditis : infection of the endothelial lining of the heart; disease can progress rapidly and is associated with high mortality rate
Wound 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
List some S. aureus toxin-mediated diseases Diseases.
Food poisoning : consumption of food contaminated with the heat-stable enterotoxin
the onset of severe vomiting, diarrhea, and stomach cramps is rapid (2 to 4 hours) but resolves within 24 hours.
intoxication is caused by the preformed toxin present
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 : 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.
How are localised S. aureus infections controlled?
Managed by incision and drainage
How are systemic S. aureus infections treated?
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
How can you prevent S. aureus infections?
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 cells are included in our innate immune response?
Neutrophils, Eosinophils, Basophils, dendritic cells and macrophages
Why must neutrophil responses be balanced?
Must be balanced to prevent infection, but also prevent damage by excessive inflammation to the host
List basically what neutrophils do.
Recruitment of neutrophils Adhesion Transmigration Priming Chemotaxis Activation Opsonisation Phagocytosis & Inflammation & degranulation
What is staphylococcus aureus?
Gram-positive bacterium
Commensal and livesharmlessly in the nose of 30% of human population.
S. aureusis an opportunistic pathogen; minor skininfections to severe and life-threatening diseases.
S. Aureus has many ways to avoid neutrophils
What is opsonisation?
Antibodies (opsonins) bind to bacterial antigens tagging them.
This allows:
1. deposition of complement in the classical complement pathway
2. neutrophils and other phagocytes the ability to detect invading microbes
How does S. aureus evade opsonisation via capsules?
Polysaccharide capsule which hides antigenic structures that can be detected by innate and adaptive immune components such as complement/antibodies
Which other bacteria evade opsonisation through polysaccharide capsules?
E. coli S. pyogenes pseudomonas aeruginosa S. pneumonia S. agalactiae
List the three ways S. Aureus evades detection by antibodies
- Polysaccharide capsule
- Incorrect opsonisation due to presence of Spa protein which binds to the incorrect region of the antibody (Fc instead of Fab)
- Secretes SSL10 which binds to Fc region of the IgG antibody
How does S. aureus evade opsonisation via SpA?
S. aureus protein binds to the IgG fc region stopping the antibody binding to the bacteria from its Fab region
Normal opsonisation is prevented so neutrophils cannot detect S. aureus - deposition of complement via the classical complement pathway is prevented
Also prevents bacteria being recognised via Fc region by the Fc receptors on neutrophils/phagocytes
How does S. aureus avoid opsonisation by SSL10?
Secretes SSL10 protein which binds to Fc region of the IgG antibody, this prevents the Fc receptors on neutrophils from detecting IgG on the surface of S. aureus
What methods can be used to avoid opsonisation?
Hide antigens Disrupt function of antibodies Prevent detection of opsonised bacteria Degrade antibodies Modify antigenicity Many bacteria use multiple
What is complement opsonisation ?
The 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.
What are the four key steps of the complement cascade?
- Initiation
- Formation of C3 convertase
- Formation of C5 convertase
- MAC formation
What are the three triggers which initiate the complement cascade?
Classical pathway > antigen-antibody complexx
Lectin pathway > Mannose-binding lectin (MBL)
Alternate pathway > bacterial surfaces (not dependent on antibodies)
Where are proteins/enzymes that are part of the complement cascade produced?
What does the cascade system do?
Its protein components (complement proteins) are 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.
What type of molecules are C5a and C3a and what do they do?
Inflammation- so recruit mast cells and basophils to release pro inflammatory molecules
chemoattractants which recruit neutrophils, eosinophils, monocytes and macrophages to the site
How does the classical complement pathway work?
Antibodies bind to antigen and the C1 complement protein binds undergoing a conformational change to form the C1QRS complex this causes a C4b2b complex (C3 convertase) to form
This breaks C3 into C3a and C3b ( an opsonin) that helps phagocytes attach to pathogens
some C3b binds to the C3 convertase complex making C4b2b3b = C5 convertase
C5b recruits C6, C7, C8, C9 causing the membrane attack complex to form
How does the lectin binding pathway work?
Mannose binding lectin protein binds to a protein called mannose found on many bacterial surfaces and has a similar shape to C1 so cleaves C4 and C2 forming the C4b2b complex (C3 convertase)
This breaks C3 into C3a and C3b ( an opsonin) that helps phagocytes attach to pathogens
some C3b binds to the C3 convertase complex making C4b2b3b = C5 convertase
C5b recruits C6, C7, C8, C9 causing the membrane attack complex to form
How does the alternative pathway work?
In the absence of C3 convertase enzyme - C3 is still being cleaved into C3a and C3b all the time
C3b is always binding to any bacterial surfaces it comes across
Factor B binds to C3b and factor D cleaves factor B into Bb and ba and Bb stays associated with C3b forming C3bBb (also C3 convertase)
This breaks C3 into C3a and C3b ( an opsonin) that helps phagocytes attach to pathogens
some C3b binds to the C3 convertase complex making C3bBb3b = C5 convertase
C5b recruits C6, C7, C8, C9 causing the membrane attack complex to form
What are four ways bacterial pathogens disrupt the complement cascade?
- Inhibit convertases
- inhibit complement components
- Degrade complement components
- Recruit host-derived regulators
How does S. aureus inhibit complement convertases and what effect does this have?
Releases SCIN which binds to C3bBb inhibiting formation of C3 convertase and thus C5 convertase
this prevents - C3b deposition, less opsonisation and no formation of MAC complex
lack of chemoattractant signalling due to lack of C3a and c5a
How does S. aureus inhibit C3 processing?
S. aureus, Efb protein binds c3d in C3 which causes a conformational change so factor B cannot bind to C3 and C3 convertase isn’t formed (C3bBb)
C3dg binding to CR2 doesnt occur either - C3d region on c3 unable to be recognised by complement receptor 2 on phagocytes so lowered detection
How does S. aureus inhibit MAC formation?
SSL7 binds to C5 and stops the MAC formation
How do neutrophils sense and respond to their environment?
Express different immune receptors on their surface or in their secretory vesicles and granules
Pathogen recognition receptors (PRRs) directly detect microbes or microbial products and this causes neutrophils to be primed or activated
What are the three different types of receptors on neutrophils that directly detect microbes and what do they detect?
TLR - conserved microbial structures
CLEC - microbial-carbohydrates
FPR - formylated peptides
What are the two types of receptors on neutrophils which indirectly detect microbes and what do they detect?
detect opsonised microbes either through
Antibody opsonised microbes - Fc receptors
Complement opsonised microbes - complement receptors
What are some activatory neutrophil receptors?
Cytokine receptors Chemoattractant receptors (cause chemotaxis)
What are some inhibitory neutrophil receptors?
LAIR receptors - prevent neutrophils being activated at the wrong time/place/extent via Inhibitory motif (ITIM)
SIGLEC receptors have inhibitory motifs which counteract activating receptors
What are some immune receptors that are both inhibitory and activatory and why are they useful?
LILR and CEACAM receptors
fine tune the immune response
How does S. aureus avoid chemotaxis and activation?
Two chemotactic receptors
C5aR detects C5a
FPR1 detects formylated peptides (fMLP)
S. aureus inhibits chemotactic receptors by releasing CHIPs (proteins) which bind to the receptors instead and prevent the agonists from binding so neutrophils do not migrate or become activated
How does S. aureus avoid phagocytosis?
IgG and IgA have phagocytic receptors
FLIPr block Fc receptors igG preventing detection of IgG opsonised bacteria
SSL5 block Fc receptors IgA
What other methods does S. aureus use to avoid neutrophils?
Kills neutrophils- and other immune cells via toxins
Express molecules that are receptor antagonist - bind and inhibit functions of activating receptors
What 4 methods do bacteria use to avoid immune evasion?
Give an example of what bacteria does this
Bind inhibitory receptors - Induces inhibitory signals and switches off neutrophil activity so neutrophils become non functional
E coli
H. pylori
Inhibit effects of antimicrobials - degranulation of neutrophils releases antimicrobial compounds used in phagocytosis
S. aureus (SPIN)
S. pneumoniae
Manipulate intracellular signalling
Modify bacterial surface - evades detection
N. meningitidis
E. coli
S. pneumoniae
What is the function of factor H?
Inhibits C3 convertases
What is the function of GBS protein IdeS?
Cleaves IgG into a non-functional form
How does antibody affect viruses?
Antibody neutralises extracellular virus by…
- blocking viral attachment proteins
- destabilises viral structure
- opsonises virus for phagocytosis
- promotes killing by complement cascade and antibody-dependent cellular cytotoxicity
- resolves lytic viral infectuin
Is IgM or IgG a more effective antiviral?
IgG
What is IgM an indicator of?
Recurrent infection
Why is secretory IgA important?
protecting mucosal surfaces
What two things in a viral infection leads to resolution?
Elimination of free virus (antibody agglutination)
and the virus producing cell (lysis)
What different ways to viruses avoid antibodies and which viruses do this?
Exist as antigenically distinct serotypes - human rhinovirus
secrete surface antigens which mop up antibody preventing it from reaching the virus -HBV and ebola
antibody dependent enhancement of disease - ie dengue virus has 4 serotypes, if reinfected with a different serotype dengue haemorrhagic fever is triggered
Antigenic shift
Antigenic drift
What are interferons?
Particles released by virally infected cells which protect against viruses
How do interferons work?
Induced by viral molecules sensed by the cell as forigen ie double stranded RNA
Interferon is secreted from the infected cell and binds to interferon receptors
IFN initiates the antiviral state in the infected cells and in surrounding cells
The antiviral state involves transcription of hundreds of genes that block viral replication ie protein kinase R
What are the three types of interferons and what interferons are in each?
Type I - IFN-alpha and beta
Type II - IFN gamma
Type III - IFN lambda
What are IFN-β and IFN-α secreted by and what receptors do they use?
IFN-βis secreted by all cells the
Plasmacytoid dendritic cells (PDCs) are specialist IFN-α secreting cells.
IFNαR receptor is present on all tissues (IFNAR is for both alpha and beta)
What is IFN-γ (gamma) produced by and what receptor does it use?
Produced by activated T cells and NK cells.
Signals through a different receptor IFN-γR.
What receptors does IFN-λ (lambda) use and where are they present
Signals through receptors IL28R and IL10-βalso known as IFN-λreceptors that are mainly present on epithelial surfaces.
How can viruses avoid interferon activity?
Viruses like Hepatitis B and Influenza virus can block production of Interferon by inhibition of IFN transcription (HBV) or Influenza virus produced a protein (NS1) that counters RNA sensing and prevents polyA processing.
What are Natural killer cells activated by in viral infections?
What do they target and how?
IFN-a and interleukin-12 which activated macrophages with IFN-y
NK cells target and kill virus infected cells - when a cell is displayed fewer than normal MHC molecules it releases toxic substances
What do macrophages and dendritic do in viral infections?
Macrophages filter viral particles from blood - Inactivate opsonised virus particles
Immatire plasmacytoid DCs produce IFN-a and other cytokines
DCs initiate and determine the nature of the CD4 and CD8 T-cell response
Both present antigen to CD4 T cells
What is the function of T cells in viral infections?
Essential for controlling enveloped and noncytolytic viral infections
recognise viral peptides presented by MHC molecules on cell surfaces
CD8 cytotocix T cells respond to viral peptide by MHC complexes on infected cell surface
