Immune Evasion

Question 1

What do neutrophils do and what is the process?

Answer 1

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

Question 2

What is antibody opsonisation?

Answer 2

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

Question 3

How do bacteria evade antibody opsonisation? (5 ways)

Answer 3

Hide antigens

Disrupt functions

Prevent detection

Degrade antibodies

Modify antigenicity

(Top three apply to S. aureus, the others don’t)

Question 4

How do bacteria hide antigens?

Answer 4

Express capsule on their surface

This is a polysaccharide which hides antigenic structures to bacteria can avoid the binding of antibodies

Question 5

How do bacteria bind to the Fc region of antibodies?

Answer 5

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

Question 6

How does S aureus inhibit detection?

Answer 6

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

Question 7

How do bacteria degrade antibodies?

Answer 7

They express proteases that can cleave antibodies into non functional forms

Question 8

How do bacteria modify their antigenicity?

Answer 8

Antigenic variation

Question 9

How do bacteria avoid complement opsonisation?

Answer 9

Inhibit convertases

Inhibit complement components

Degrade complement components

Recruit host derived regulators

Question 10

What is completely opsonisation?

Answer 10

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:

1. Initiation
2. Formation of C3 convertase
3. Formation of C5 convertase
4. MAC formation

Question 11

How to bacteria inhibit convertases?

Answer 11

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

Question 12

How do bacteria inhibit complement components?

Answer 12

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

Question 13

How do bacteria degrade complement components?

Answer 13

Express proteases that cleave complement components making them non functional and stopping the complement cascade

Question 14

How do bacteria recruit host derived complement regulators?

Answer 14

Some bacteria can recruit factor H (FH) to the surface, this can inactive C3b

Other bacteria can rectuit C4BP, which degrades C2a

Question 15

How to bacteria evade neutrophil functions?

Answer 15

Inhibit chemotaxis

Inhibit detection of bacteria

Kill neutrophils

Stimulate inhibitory receptors

Disrupt cellular signalling

Question 16

How do neutrophils function?

Answer 16

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

Question 17

How do bacteria inhibit chemotaxis?

Answer 17

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

Question 18

How do bacteria prevent phagocytosis?

Answer 18

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

Question 19

How can S. aureus directly kill neutrophils?

Answer 19

S. Aureus secretes a number of toxins

These bind to the surface of nutropils which leads to their lysis

Eg the PVL toxin

Question 20

What are some of the roles of antibodies against viruses?

Answer 20

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

Question 21

What is required for resolution of a viral infection?

Answer 21

Elimination of free virus (antibody agglutination)

Elimination of the virus producing cells (viral or immune cell mediated lysis)

Question 22

How do some viruses escape antobody detection?

Answer 22

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)

Question 23

What are interferons?

Answer 23

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

Question 24

What are type I interferons?

Answer 24

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

Question 25

What are type II interferons?

Answer 25

IFN gamma

Produced by activated T cells and NK cells

Signals through a different receptor IFN gamma R

Question 26

What are type III interferons?

Answer 26

IFN lambda

Signals through receptors IL28R and IL10- beta, also know and IFN lambda receptors, these are mainly present on epithelial surfaces

Question 27

How do viruses block production of interferon?

Answer 27

Hep B and influenza

Inhibit IFN transcription By producing a protein (NS1) that counters RNA sensing and prevents PolyA processing

Question 28

What do natural killer cells do?

Answer 28

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

Question 29

What do macrophages and dendritic cells do?

Answer 29

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

Question 30

What to T cells do?

Answer 30

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

Question 31

How can viruses impair lymphocyte functions?

Answer 31

HIV kills CD4 cells and alters macrophage function

Herpes simplex virus can prevent CD8 killing