Immune Evasion Flashcards
S aureus
Grow aerobically or anaerobically
Has polysaccharide capsule that protects bacteria from phagocytosis
Cell surface proteins mediate adherence of bacteria to host cells
Catalase protects from peroxides released by neutrophils and macrophages
Coagulase converts fibrinogen to insoluble fibrin that forms clots and protects it from phagocytosis
How do neutrophils work
1) Microbes enter the body and become opsonised with antibodies and complement
2) Results in production of gradient of C3a and C5a as well as bacterial proteins and peptides
3) C3a and C5a bind to their receptors (C3aR, C5aR respectively) on endothelial cells which causes endothelial cells to express ICAM at their surface
4) When neutrophils contact endothelial cells they detect this increase in ICAM and adhere to ICAM receptors, roll along surface of endothelium then transmigrate across endothelial layer
5) They become primed by gradient of C3a and C5a/bacterial proteins and peptides
6) Migrate towards complement components and bacterial proteins (where microbes are) via chemotaxis
7) 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)
8) Neutrophils also recruit other immune cells (part of inflammatory process)
Antibody opsonization
Antibodies bind to pathogens
C3b activates neutrophils to engulf pathogens
Capsule expression
Hides antigens
E. coli,s.pyogenes,s.pneumonia,s.agalactiae
Protein A
Bunds IgG antibodies via fc region preventing opsonisation so neutrophils can’t detect s.aerues
Other bacteria include sbi
SSL10
Secreted protein that binds to the Fc region of IgG prevents neutrophil detection of antibody
IdeS
Protease cleaves IgG antibodies which prevents antibodies binding to bacteria
Antigenic variation
Means antibodies can no longer recognize bacteria eg gonorrhoea expresses opa protein which can switch into diff antigenic variations
Complement system
Complement system is composed of large number of proteins that react with one another to opsonise pathogens or to directly kill them by membrane attack complex (MAC) formation
Key step of complement opsonisation
Deposition of C3b onto surface of microbe which can be detected by complement receptors expressed on neutrophils/other phagocytes which can phagocytose the microbe
4 general steps of complement cascade
- Initiation
- Formation of C3 convertase
- Formation of C5 convertase
- MAC formation
What are the 3 initiation pathways that all result in formation of C3 convertase?
Classical pathway- antibodies bind to antigens resulting in complex C1qrs forming which activate the C3 convertase C4bC2b
Lectin MBL pathways- MBL binds to mannose forming a complex with MASPcausing C3 convertases production
Alternative pathway-C3b is sporadically deposited onto microbes surface,recruitment of additional factor B causes formation of c3 convertase C3bBb
Lectin/MBL pathways
MBL (mannose binding lectin) detects and binds carbohydrates (mannose) on surface of microbes and forms a complex with MASP- this results in generation of C4bC2b complex (a C3 convertase)
MBL made in the liver
Alternative pathway
- C3b is sporadically deposited onto surface of microbe
- Recruitment of additional factor B results in formation of the C3 convertase C3bBb
What do both C3 convertases do
- Convert C3 in C3a and C3b
- Produces more C3b when factor B and C3 work together.
- Results in formation of the C5 convertase C3bBbC3b which degrades C5 into C5a and C5b
What happens if C5b is deposited on microbial surface
Recruits C6, C7, C8 and C9 which form the Membrane Attack Complex (MAC)
How do bacteria evade complement opsonisation
SCIN binds to C3bBb and inhibits formation of C3 comvertsse and C5 convertase (S.aureus)
Efb binds to C3d in c2 which induces a conforms change preventing binding of factor B to C3 and C3dg binding to CR2 (s.aerues)
SSL7 binds to C5 preventing conversion into C5a and C5b inhibiting MAC formation (s.aerues)
Sbi binds to IgG to prevent recognition by c1which inhibits C3 convertases (s.aerues does thus by Sbi expression)
Air protein degrades C3 preventing C3a formation and c3b deposition
How are neutrophils primed or activated
Pathogen recognition receptors which detect microbes or microbial products
What 3 different types of PRRs exist
TLR- toll like receptors that detect conserved microbial structures
CLEC- c type lectin detect microbial carbohydrate
FPR- Formylated peptide receptors which detect formylated peptides
How can neutrophils indirectly detect bacteria
Microbes can be opsonised by antibodies or complement and neutrophils can detect opsonised microbes through Fc receptors or complement receptors that detect antibody opsonised and complement opsonised microbes respectively
ITAMS are activating motifs in cytoplasmic tails of Fc receptors
What are the 4 different classes immune receptors that modulate function?
Activatory receptors- enhance immune cell activity
Inhibitory receptors-suppress immune cell activity preventing neutrophils from being activated at the wrong time wrong place or to wrong extent eg LAIR receptors
Cytokine receptor-detect cytokines and therefore signal neutrophils to become more or less activated
Chemoattractant- for neutrophils to perform chemotaxis and migrate to site if infection
Why do some receptors have both activating and inhibitory members
Fine tune immune responses
How is chemotaxis inhibited
CHIPs bind to C5aR and FPR1 preventing binding of C5a and fMLP
How is phagocytosis inhibited
- S. aureus expresses FLIPr molecule that binds to and thus inhibits Fc γ receptors which means the receptors can’t interact with IgG antibodies bound to S. aureus
- S. aureus expresses SSL5 molecule that binds to and thus inhibits Fc α receptors which means the receptors can’t interact with IgA antibodies bound to S. aureus
Kill neutrophils
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
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 that bind to inhibitory receptors and activate them which induces inhibitory signals and switches off neutrophil activity so they can’t perform their function of killing the microbe- enhances bacterial survival
Inhibit effect of anti microbial
Neutrophils have granules with antimicrobial compounds that are released on degranulation or utilised within phagolysosome
S. aureus and other proteins express proteins that can inhibit the effects of these antimicrobials to increase bacteria chance of survival upon degranulation/phagocytosis
Manipulate intracellular signalling
Used by intracellular bacterial pathogens
Modify bacterial surface
Allows bacteria to evade detection via neutrophils like N meningitidis that can switch expression of Opa proteins or E. coli that can switch expression of O and K antigens
What are the roles of antibodies against viruses
Neutralizing Extracellular virus- block viral attachment proteins ,destabilizes viral structure
Opsonises virus for phagocytosis
Promote killing of target cell by complement cascade and antibody dependant cellular cytotoxicity
Resolves lyric viral infections
Blocks viremic spread to target tissues
Role of antibodies IgM,IgG,IgA
- 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.
How do viruses escape antibody recognition
- Human rhinoviruses that cause the common cold exist as hundreds of antigenically distinct serotypes
- HIV exists as multiple clades or quasi-species
- Hep B 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 the Fc-Receptor. This triggers Dengue Haemorrhagic Fever.
- Influenza viruses mutate and evolve to change year on year, antigenic drift.
- Influenza viruses can also acquire completely new antigens by reassortment with animal viruses; This is called antigen shift and can lead to pandemics.
Interferons
Virally infected cells produce and release interferons
Bind to IFN receptors activating the antiviral state in the infected cell and surrounding cells
IFN activates NK cells and systemic anti viral responses
Different types of IFN
Type I IFNs are IFN-α and IFN-β
IFNb secreted by all cells and IFN ar receptor present in all tissues
IFNa has 13 isotopes and IFNb made by one gene
Type 2 is IFN-γ (IFN-gamma). It actually ages macrophages. Produced by T cells and NK cells
Type III– IFN is IFN-λ (IFN-lambda)
- Signals through receptors IL28R and IL10-β aka IFN-λ receptors that are mainly present on epithelial surfaces.
How do viruses combat IFN
Hep B and Influenza virus can block production of IFN by inhibition of IFN transcription (HBV) or Influenza virus produced a protein (NS1) that counters RNA sensing and prevents polyA processing
How do viruses fight back against T cells
- HIV kills CD4 T cells and alters macrophage function.
- Herpes simplex virus can prevent CD8 T-cell killing
How do NK cells protect against viruses
Activate IFN-a and interleukin 12
- They 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 cells which kills virus infected cell
How do macrophages protect against viruses
- Macrophages filter viral particles from blood.
- Macrophages inactivate opsonized virus particles.
- Macrophages present antigen to CD4 T cells.
How do dendritic cells protect against viruses
- Immature and plasmacytoid DCs produce IFN-α and other cytokines.
- DCs initiate and determine the nature of the CD4 and CD8 T-cell response.
- DCs present antigen to CD4 T cells.
What recepto do neutrophils express when selections bind to endothelial cells
PSGL-1
How do s aureus evade antibody response
Bacteria express capsules to hide antigens
Protein A binds to Fc region of antibodies not fab region preventing opsonisation
Proteases cleave or modify antibody preventing opsonisation eg SAK
Flipr binds to Fc region preventing opsonisation
What bacterial endotoxins does the alternative pathway recognize
Lipopolysaccahrides
Gram negative bacteria outer membrane
Factor H
Inhibits C3 convertases
Factor B and D
Involved in alternative pathway
Leads to C3b formation
How do T cells affect viral infection
They control enveloped and noncytolytic viral infection
T cells recognize viral peptides eg linear epitopes (from glycoproteins or nucleoproteins) on MHC
When is Cd4 TH2 responses detrimental
If they prematurely limit Th1 inflammatory and cytolytic responses
