Immune Evasion Flashcards
What do neutrophils do and what is the process?
Foreign bacteria are opsinised by antibodies and complement
Produces a gradient of bacterial proteins and C3a and C5a
C3a and C5a bund to C3aR and C5aR on endothelial cells. Results in a change in expression of ICAM on the endothelial surface.
Neutrophils In the blood adhere to ICAM receptors and migrate across the endothelial layer
Neutrophils are primed but the C3a C5a gradient
They undergo chemotaxis towards the complement components or the bacterial proteins (so towards the infection)
They are then activated
Then they perform their effector functions (phagocytosis/ degranulation) and cause inflammation
What is antibody opsonisation?
Antibodies bind bacterial antigens allowing
1) the deposition of compliment one the classical complement pathway
2) neutrophils and other phagocytes the ability to detect invading microbes
So bacteria have evolved many ways to evade antibody detection
How do bacteria evade antibody opsonisation? (5 ways)
Hide antigens
Disrupt functions
Prevent detection
Degrade antibodies
Modify antigenicity
(Top three apply to S. aureus, the others don’t)
How do bacteria hide antigens?
Express capsule on their surface
This is a polysaccharide which hides antigenic structures to bacteria can avoid the binding of antibodies
How do bacteria bind to the Fc region of antibodies?
Fc = constant region
Eg S. aureus protein A (SpA)
Is exhibited on bacteria surface
This binds to antibodies via the Fc region (not the Fab region)
So SpA prevents normal opsonisation, so complement isn’t activated, and neutrophils can’t detect S. aureus
How does S aureus inhibit detection?
Secreted SSL10 protein
If S aureus is opsinised by antibodies, these proteins are secreted and bind to the Fc region of IgG
This prevents deposition of the complement pathways and stops antibodies in the surface of neutrophils and other phagocytes from detecting IgG on the surface of S. aureus
How do bacteria degrade antibodies?
They express proteases that can cleave antibodies into non functional forms
How do bacteria modify their antigenicity?
Antigenic variation
How do bacteria avoid complement opsonisation?
Inhibit convertases
Inhibit complement components
Degrade complement components
Recruit host derived regulators
What is completely opsonisation?
Complement 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
One key step: deposition of C3b onto the surface of the microbe. This is detected by its receptors on neutrophils and other phagocytes. This results in direct phagocytosis or killing of the microbe
Key steps involve:
- Initiation
- Formation of C3 convertase
- Formation of C5 convertase
- MAC formation
How to bacteria inhibit convertases?
Eg S. aureus secretes SCIN (a protein) into the local environment
SCIN bind to C3bBb (part of the alternate complement pathway). This inhibits the formation of C3 convertase and C5 convertase
This prevents C3b deposition, C3a deposition and C5a deposition
How do bacteria inhibit complement components?
Expresses inhibitors of C3 processing
S aureus secretes Efb
This binds the C3d region in C3 which indices a conformational change
This prevents factor B from binding to C3, and C3dg binding you CR2 (expressed on phagocytes so there is less phagocyte action)
This essentially shuts down the complement cascade so it is no longer able to function
How do bacteria degrade complement components?
Express proteases that cleave complement components making them non functional and stopping the complement cascade
How do bacteria recruit host derived complement regulators?
Some bacteria can recruit factor H (FH) to the surface, this can inactive C3b
Other bacteria can rectuit C4BP, which degrades C2a
How to bacteria evade neutrophil functions?
Inhibit chemotaxis
Inhibit detection of bacteria
Kill neutrophils
Stimulate inhibitory receptors
Disrupt cellular signalling
How do neutrophils function?
They express hundreds of different immune receptors at their surface or in their secretory vesicles and granules
This allows them to sense and respond to their environment
Many of these receptors are pathogen recognition receptors (PRRs). Binding to these causes the neutrophils to become primed or activated
They also detect opsinised microbes through Fc receptors or complement receptors
They also have a diverse range of immune receptors that can be activators or inhibitory to enhance or surpress immune cell activity where needed
How do bacteria inhibit chemotaxis?
Neutrophils express C5aR and FPR1 receptors, these are both very important for chemotaxis
S. Aureus expresses a protein called CHIPs. This binds to both of the above receptors and prevents their interaction with C5a and fMLP
This means neutrophils don’t migrate up the gradient to the local site of infection
How do bacteria prevent phagocytosis?
Neutrophils express a lot of phagocytic receptors, such as Fc receptors.
S. Aureus can prevent Fc mediated phagocytosis by expressing molecules that bind to these molecules
Eg it secretes FLIPr which binds to Fc gamma receptors. This blocks the binding of IgG-opsinised bacteria
This reduces antibody mediated phagocytosis and killing of S. aureus
It also secretes SSL5 which binds to Fc alpha receptors. Carrying out a similar function
How can S. aureus directly kill neutrophils?
S. Aureus secretes a number of toxins
These bind to the surface of nutropils which leads to their lysis
Eg the PVL toxin
What are some of the roles of antibodies against viruses?
Neutralises extracellular virus
Opsonises boris for phagocytosis
Promotes killing of the virus through complement cascade and antibody dependent cytotoxic activity
Resolved lyric viral infection
Blocks spread to target tissue
IgM is an indicator of current/ recent infection
IgG is a more effective antiviral than IgM
Secretory IgA is important for protecting mucosal surfaces
What is required for resolution of a viral infection?
Elimination of free virus (antibody agglutination)
Elimination of the virus producing cells (viral or immune cell mediated lysis)
How do some viruses escape antobody detection?
Rhinoviruses exist as hundreds of antigenically distinct serotypes
HIV exists as multiple clades (quasi-species)
Hep B and Ebola virus encode secreted antigens that mop up antibody so they don’t bind to the virus
Dengue exists as 4 serotypes. Previous infection followed by a different infection can lead to antobody dependent enhancement of disease as virus enters immune cells via antibody and the Fc receptor. This triggers dengue haemorrhagic fever
Influenza virus can undergo antigenic shift and antigenic drift (this can make finding a vaccine difficult)
What are interferons?
Small proteins Produced by virally infected cells, they play a role in the immune response
IFN is induced by molecules made by viruses that are sensed by the host cell as being foreign
It is secreted from the infected cell and binds to interferon receptors. It initiates the antiviral state in the infected cells and surrounding cells
The antiviral state involves transcription of hundreds of genes that block viral replication (eg protein kinase R)
Interferon also activates natural killer cells and systemic antiviral responses
What are type I interferons?
Type I: IFN alpha and beta
IFN beta is secreted by all cells and the IFN alpha R receptor is present on all cells
Plasmacytoid dendritic cells are specialist IFN alpha secreting cells
There is only one gene for IFN beta but 13/14 isotopes for IFN alpha
What are type II interferons?
IFN gamma
Produced by activated T cells and NK cells
Signals through a different receptor IFN gamma R
What are type III interferons?
IFN lambda
Signals through receptors IL28R and IL10- beta, also know and IFN lambda receptors, these are mainly present on epithelial surfaces
How do viruses block production of interferon?
Hep B and influenza
Inhibit IFN transcription By producing a protein (NS1) that counters RNA sensing and prevents PolyA processing
What do natural killer cells do?
Activated by IFN-a and IL-12, which activate macrophages with IFN-gamma
They target and kill virus infected cells (especially enveloped viruses)
When they find a cell displaying fewer than normal MHC molecules (eg HSV) it releases toxic substances, similarly to cytotoxic T cells. This kills the virally in extend cell
What do macrophages and dendritic cells do?
Macrophages Filter viral particles from the blood and inactivate opsinised virus particles
Immature and plasmacytoid DCs produce IFN a and other cytokines
DCs initiate and determine the nature of the CD4 and CD8 T cell response
DCs and macrophages present antigen to CD4 cells
What to T cells do?
Essential for controlling enveloped and non cytolytic viral infections
They recognise viral peptides presented by MHC molecules on cell surfaces
Antigenic viral peptides can come from any viral protein
CD8 cells respond to viral peptide : class I MHC protein complexes on the infected cell surface
CD4 Th2 responses may be detrimental if they prematurely limit the Th1 inflammatory and cytolytic responses
How can viruses impair lymphocyte functions?
HIV kills CD4 cells and alters macrophage function
Herpes simplex virus can prevent CD8 killing
