4.7 - Immune Evasion Flashcards
1
Q
Staphylococcus aureus
A
- gram positive bacteria that is commensal and lives harmlessly in nose of 30% of humans
- opportunistic pathogen that can cause minor skin infections to severe/life-threatening diseases
- diseases caused by S. aureus are divided into two groups:
- localised pyogenic (pus-producing) diseases characterised by tissue destruction mediated by hydrolytic enzymes and cytotoxins
- diseases mediated by toxins that function as superantigens producing systemic diseases
2
Q
Properties of Staphylococcus aureus
A
- ability to grow aerobically and anaerobically over a wide range of temperatures, and in the presence of a high concentration of salt (bacteria is a common cause of food poisoning)
- polysaccharide capsule that protects bacteria from phagocytosis
- cell surface proteins (protein A, clumping factor proteins) that mediate adherence of bacteria to host tissues
- catalase protects them from peroxides produced by neutrophils and macrophages
- coagulase converts fibrinogen into fibrin that forms clots and can protect S. aureus from phagocytosis
- contain hydrolytic enzymes and cytotoxins: lipases, nucleases and hyaluronidase that cause tissue destruction; cytotoxins (alpha, beta, delta, gamma, leucocidin) that lyse erythrocytes, neutrophils, macrophages etc
- toxins: enterotoxins (heat-stable and acid-resistant toxins responsible for food poisoning), exfoliative toxins A and B (which cause the superficial layers of skin to peel off - scalded skin syndrome), and toxic shock syndrome toxin (heat and protease-resistant toxin that mediates multiorgan pathology)
3
Q
Streptococcus pyogenes
A
- gram positive bacterium
- can live harmlessly in the throat of humans
- opportunistic pathogen - can cause a range of diseases including pharyngitis (Strep throat), skin infections, scarlet fever and sepsis
- evolved many sophisticated mechanisms to evade neutrophils
4
Q
Pathogen diversity
A
- huge diversity in bacterial microbes
- immune responses developed mechanisms to detect this diverse range of bacteria
- bacteria often share common features - detected by immune response e.g. LPS in gram-negative bacteria, LTA in gram-positive bacteria, flagella on certain bacteria
- some microbes have evolved mechanisms which enhance survival in their host
- these immune evasion mechanisms contribute to bacterial pathogenesis
5
Q
The role of the innate immune system
A
- first line of defence against pathogens
- very efficient and detecting and killing invading microbes
- includes neutrophils, basophils, eosinophils, dendritic cells and macrophages
6
Q
Neutrophils - key points
A
- most abundant leucocyte (50-70%) in blood
- recruited to areas of infection
- detect microbes
- perform effector functions –> kill microbes
- considered ‘simple’ immune cells
- neutrophil responses must be balanced to prevent infection, but also prevent damage (inflammation) to the host
7
Q
How do neutrophils work?
A
- microbes enter the body and become opsonised with antibodies and complement
- results in production of gradient of C3a and C5a (complement components) as well as bacterial proteins and peptides
- C3a and C5a bind to their receptors (C3aR and C5aR respectively) on endothelial cells, which causes endothelial cells to express ICAM on their surface –> neutrophil recruitment
- when neutrophils contact endothelial cells they detect this increase in ICAM and adhere to ICAM receptors, roll along the surface of endothelium, then transmigrate across the endothelial layer
- they become primed by gradient of C3a and C5a / bacterial proteins and peptides
- migrate towards complement components and bacterial proteins (where microbes are) via chemotaxis
- become activated and perform effector functions –> can be phagocytosis (ingestion and killing pathogens within phagosome by antimicrobial molecules) or degranulation (reactive O2 species or antimicrobial molecules produced)
- neutrophils also recruit other immune cells (part of inflammatory response)
8
Q
Bacterial evasion of antibody opsonisation
A
- bacteria express surface and secreted proteins that interfere with innate immune responses
What is antibody opsonisation?
- antibodies bind bacterial antigens allowing:
- deposition of complement in the classical complement pathway
- neutrophils and other phagocytes the ability to detect invading microbes
- bacteria have evolved many mechanisms to evade antibody opsonisation
9
Q
Capsule expression - evading antibody opsonisation
A
- bacteria can express a capsule on their surface –> helps hide antigenic structures that can be detected by innate and adaptive components e.g. complement and antibodies
- done by S. aureus along with E.coli, S. pyogenes, S. pneumonia, S. agalactiae, Pseudomonas aeruginosa
- MAIN FUNCTION - HIDE ANTIGENS
10
Q
Binding of surface proteins to Fc region of antibodies - evading antibody opsonisation
A
- S. aureus protein A (Spa) and M surface proteins bind antibodies via their Fc region not their Fab region
- this prevents normal opsonisation (prevents deposition of complement onto bacterial surface via classical complement pathway) = neutrophils cannot detect S. aureus or S. pyogenes
- other bacteria express surface proteins that bind to antibodies including Streptococcus dysgalactiae (protein G binds IgG), Peptostreptococcus magnus (protein L binds IgG) and Streptococcus agalactiae (beta protein binds IgA)
- MAIN FUNCTION - DISRUPT FUNCTION
11
Q
Expressing SSL10 - evading antibody opsonisation
A
- SSL10 is a secreted protein that binds to Fc region of IgG antibodies that opsonise S. aureus and prevents Fc receptors on neutrophils from detecting these IgG receptors on S. aureus surface
- also prevents deposition of complement via classical complement pathway
- another protein called Sak also does this
- MAIN FUNCTION - PREVENT DETECTION
12
Q
Proteases that cleave antibodies - evading antibody opsonisation
A
- proteases cleave / modify antibodies into non-functional forms (e.g. S. pyogenes expresses IdeS protease which cleaves IgG antibodies at the hinge region = reduced classical complement response)
- prevents normal opsonisation and therefore neutrophils cannot detect S. pyogenes
- MAIN FUNCTION - DEGRADE ANTIBODIES
13
Q
Antigenic variation - evading antibody opsonisation
A
- switching proteins/capsules on surface of bacteria means antibodies that recognise first surface structure are unable to recognise them now
- e.g. N. gonorrhoeae expresses Opa protein –> different antigenic variations
- MAIN FUNCTION - MODIFY ANTIGENICITY
14
Q
Bacterial evasion of complement activation
A
- 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)
- the key step of the process is deposition of C3b onto surface of microbe which can be detected by complement receptors expressed on neutrophils/phagocytes which can phagocytose the microbe
- key steps of complement cascade:
- initiation
- formation of C3 convertase
- formation of C5 convertase
- MAC formation
15
Q
What are the three initiation pathways that result in the formation of C3 convertase? (complement cascade)
A
- classical pathway - antibodies bind to antigens resulting in complex C1qrs forming which activate the C3 convertase, C4bC2b
- lectin / MBL pathway - MBL (mannose binding lectin made in liver) is able to detect and bind carbohydrates or sugars on surface of microbes and form a complex with MASP –> generation of C4bC2b
- alternative pathway - C3b is sporadically deposited onto surface of microbe, recruitment of additional factor B –> C3bBb (C3 convertase)
- both C3 convertases produce more C3b when factor B and C3 work together, resulting in formation of C5 convertase C3bBbC3b which degrades C5 –> C5a and C5b
- deposition of C5b on microbial surface –> recruits C6, C7, C8 and C9 which form MAC
16
Q
Proteases degrade C3 - evading complement opsonisation
A
- S. aureus Aur and S. pyogenes SpeB are proteases that degrade C3
- this prevents:
1. C3b deposition (phagocytes unable to detect C3b opsonised microbes)
2. C3a formation (lower chemoattractant signals for recruitment of immune cells to infection)
3. C5a formation - MAIN FUNCTION - DEGRADE COMPLEMENT COMPONENTS
17
Q
Bacteria inhibit C3 or C5 convertases - evading complement opsonisation
A
- S. aureus SCIN protein binds C3bBb and inhibits formation of C3 convertase and C5 convertase
- this prevents:
1. C3b deposition (phagocytes unable to detect C3b opsonised microbes)
2. C3a formation (lower chemoattractant signals for recruitment of immune cells to infection)
3. C5a formation - MAIN FUNCTION - INHIBIT C3/C5 CONVERTASES
18
Q
Bacteria recruit negative regulators - evading complement opsonisation
A
- S. aureus recruits factor H
- S. pyogenes recruits factor H and C4BP
- factor H inactivates C3b on bacterial surface
- C4BP is associated with factor I and degrades C2a from C3 convertases (C4b2a)
- MAIN FUNCTION - ACQUIRE HOST-DERIVED COMPLEMENT REGULATORS
19
Q
Goal of complement opsonisation strategies
A
- some other proteases cleave complement components
- goal is to ensure S. aureus is not killed by MAC and less C3b deposited onto surface of bacteria which could be detected by neutrophils/phagocytes
20
Q
Bacterial evasion of neutrophil functions - how do neutrophils respond to environment?
A
- neutrophils express hundreds of different immune receptors at their surface / in secretory vesicles (SVs) and granules
- immune receptors allow neutrophils to sense and respond to their environment - detect microbes, microbial products or self proteins
- pathogen recognition receptors (PRRs) directly detect microbes/microbial products –> neutrophils are primed/activated
- examples of PRRs: TLR receptors (detect conserved microbial structures), CLEC receptors (detect microbial carbohydrates), FPR receptors (detect formylated peptides)
- indirect detection - microbes can become opsonised by antibodies/complement –> neutrophils detect opsonised microbes through Fc receptors or complement receptors
21
Q
Examples of neutrophil immune receptors
A
- activatory receptors - enhance immune cell activity
- inhibitory receptors - suppress immune cell activity (prevent neutrophil activation at wrong time/place/extent)
- cytokine receptors - detect cytokines and signal neutrophil to become more or less activated
- chemoattractant receptors - for neutrophils to perform chemotaxis and to migrate towards site of infection
- some receptors have both activating and inhibitory members to fine-tune immune responses
22
Q
Bacteria inhibit chemotaxis - evading neutrophil functions
A
- this is key in reducing amount of neutrophils that arrive at the site of infection, allowing bacteria to survive
- neutrophils express two vital chemotactic receptors - C5aR (detects C5a) and FPR1 (detects formylated peptides - fMLP - produced by microbes)
- S. aureus expresses a protein called CHIPs that binds C5aR and FPR1 and prevents binding of their agonists (C5a and fMLP)
- S. pyrogenes expresses SpyCEP which cleaves CXCL8 and prevents its binding to CXCR1/2
- means neutrophils are not able to sense and become activated by these agonistic ligands and not able to migrate to sites of infection up concentration gradient
23
Q
Bacteria inhibit phagocytosis - evading neutrophil functions
A
- neutrophils express different phagocytic receptors including Fc receptors to detect IgG and IgA opsonised microbes
- S. aureus expresses FLIPr molecule that binds to and thus inhibits Fc gamma receptors = receptors cannot interact with IgG antibodies bound to S. aureus
- S. aureus expresses SSL5 molecule that binds to and thus inhibits Fc alpha receptors = receptors cannot interact with IgA antibodies bound to S. aureus
- bacteria have increased survival chance as antibody mediated phagocytosis and killing has been decreased
24
Q
Bacteria can kill neutrophils - evading neutrophil functions
A
- S. aureus can express different toxins that bind to receptors at surface of neutrophils which results in their lysis
- e.g. PVL toxin that kills human neutrophils
- results in fewer neutrophils at site of infection that can detect and kill bacteria, reducing phagocytosis and killing
25
Bacteria can interfere with neutrophil receptors - evading neutrophil functions
- inhibit activating receptors - S. aureus expresses molecules at surface which bind to activating receptors and blocks their function
- activate inhibitory receptors - some bacteria express proteins which bind to inhibitory receptors and activate them = induces inhibitory signals and switches off neutrophil activity = cannot kill microbe, enhancing bacterial survival
26
Bacteria can inhibit effects of antimicrobials - evading neutrophil functions
- neutrophils have granules with antimicrobial compounds that are released on degranulation or utilised within phagolysosome
- S. aureus expresses proteins that can inhibit the effects of these antimicrobials to increase bacteria chance of survival upon degranulation/phagocytosis
27
Bacteria can manipulate intracellular signalling - evading neutrophil functions
- used by intracellular bacterial pathogens
- can result in reduced phagocytosis etc
28
Bacteria can modify their surfaces - evading neutrophil functions
- allows bacteria to evade detection by neutrophils
- e.g. N. meningitidis can switch expression of Opa proteins, E. coli can switch expression of O and K antigens
- masks antigenic structures, shielding from neutrophils and antibodies
29
Immune evasion by viruses
- ultimate goal of the immune response to a viral infection is to eliminate both the virus and host cells harbouring / replicating the virus
- failure to resolve infection may lead to persistent / chronic infection or death
- resolution of infection requires elimination of free virus (antibody agglutination) and the virus-producing cell (viral or immune cell-mediated lysis)
30
What are the roles of antibodies against viruses?
- neutralises extracellular virus - blocks viral attachment proteins (e.g. glycoproteins, capsid proteins) and destabilises the viral structure
- opsonises virus for phagocytosis
- promotes killing of target cell by the complement cascade and antibody-dependent cellular toxicity
- resolves lytic viral infections
- blocks viremic spread to target tissue
- IgM is an indicator of recent or current infection
- IgG is a more effective antiviral than IgM
- secretory IgA is important for protecting mucosal surfaces
31
How do viruses escape antibody recognition?
- human rhinoviruses that cause common cold exist as hundreds of antigenically distinct serotypes (makes finding a cold vaccine difficult)
- HIV exists as multiple clades or quasi-species
- hepatitis B virus (HBV) and Ebola virus encode secreted surface antigens that mop up antibody, stopping it reaching virus particles or infected cells
- dengue virus exists as 4 serotypes - previous infection with one serotype followed by infection with a different serotype can lead to antibody dependent enhancement of disease as virus enters immune cells via antibody and Fc-receptor - triggers dengue haemorrhagic fever
- influenza viruses mutate and evolve to change year on year - antigenic drift (new vaccine needed each year)
- influenza viruses can also acquire completely new antigens by reassortment with animal viruses - antigenic shift --> pandemics
32
Interferons (IFNs) - how do they help against viruses?
- virally infected cells produce and release small proteins called interferons
- IFN is induced by molecules made by viruses that are sensed by the cell as foreign or in the wrong cellular location (e.g. double stranded RNA, RNA without 5' cap, DNA in cytoplasm)
- IFN secreted from infected cell and binds to interferon receptors (on other cells) - IFN initiates the antiviral state in the infected cells and surrounding cells
- antiviral state involves transcription of hundreds of genes that block viral replication e.g. 2'5' oligoadenylate synthetase and protein kinase R
- IFN activates natural killer cells and systemic antiviral responses
33
What are the different types of IFN?
Type I - IFN-alpha and IFN-beta
- IFN-B secreted by all cells, IFN-aR receptor is present on all tissues
- plasmacytoid dendritic cells (PDCs) are specialist IFN-a secreting cells
- one gene for IFN-B, but 13/14 isotopes of IFN-a
Type II - IFN-gamma
- produced by activated T cells and NK cells
- signals through a different receptor IFN-yR
Type III - IFN-lambda
- signals through receptors IL28R and IL10-beta AKA IFN-lambda receptors that are mainly present on epithelial surfaces
34
How do viruses combat IFN?
Viruses like hepatitis B and influenza virus can block production of IFN by inhibition of transcription (HBV) or influenza virus produces a protein (NS1) that counters RNA sensing and prevents polyA processing
35
How do T cells protect against viruses?
- T cells are essential for controlling enveloped and noncytolytic viral infections
- T cells recognise viral peptides presented by MHC molecules on cell surfaces
- antigenic viral peptides (linear epitopes) can come from any viral protein (e.g. glycoproteins, nucleoproteins)
- CD8 cytotoxic T cells respond to viral peptide: class I MHC complexes on infected cell surface
- CD4 TH2 responses may be detrimental if they prematurely limit the TH1 inflammatory and cytolytic responses
36
How do viruses fight back against T cells?
- viruses that result in chronic infections often have potent ways to counter T cell response
- many large DNA viruses e.g. herpes virus including herpes simplex HSV and cytomegalovirus CMV encode proteins that interfere with the MHC antigen processing pathway
- viruses can impair lymphocyte function:
1. HIV kills CD4 T cells and alters macrophage function
2. herpes simplex virus can prevent CD8 T-cell killing
37
How do natural killer cells protect against viruses?
- NK cells are activated by IFN-a and interleukin-12, which activate macrophages with IFN-y
- NK cells target and kill virus-infected cells (especially enveloped viruses)
- when the NK cell finds a cell displaying fewer than normal MHC molecules (e.g. cytomegalovirus or herpes simplex virus infected) it releases toxic substances (similar to cytotoxic T cell) which kill the virally-infected cell
38
How do macrophages protect against viruses?
- macrophages filter viral particles from blood
- macrophages inactivate opsonised virus particles
- macrophages present antigen to CD4 T cells
39
How do dendritic cells protect against viruses?
- immature and plasmacytoid DC cells produce IFN-a and other cytokines
- DCs initiate and determine the nature of the CD4 and CD8 T-cell response
- DCs present antigen to CD4 T cell
