Immune Evasion Flashcards

1
Q

S aureus

A

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

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2
Q

How do neutrophils work

A

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)

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3
Q

Antibody opsonization

A

Antibodies bind to pathogens
C3b activates neutrophils to engulf pathogens

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4
Q

Capsule expression

A

Hides antigens
E. coli,s.pyogenes,s.pneumonia,s.agalactiae

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5
Q

Protein A

A

Bunds IgG antibodies via fc region preventing opsonisation so neutrophils can’t detect s.aerues
Other bacteria include sbi

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6
Q

SSL10

A

Secreted protein that binds to the Fc region of IgG prevents neutrophil detection of antibody

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7
Q

IdeS

A

Protease cleaves IgG antibodies which prevents antibodies binding to bacteria

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8
Q

Antigenic variation

A

Means antibodies can no longer recognize bacteria eg gonorrhoea expresses opa protein which can switch into diff antigenic variations

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9
Q

Complement system

A

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

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10
Q

Key step of complement opsonisation

A

Deposition of C3b onto surface of microbe which can be detected by complement receptors expressed on neutrophils/other phagocytes which can phagocytose the microbe

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11
Q

4 general steps of complement cascade

A
  • Initiation
  • Formation of C3 convertase
  • Formation of C5 convertase
  • MAC formation
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12
Q

What are the 3 initiation pathways that all result in formation of C3 convertase?

A

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

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13
Q

Lectin/MBL pathways

A

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

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14
Q

Alternative pathway

A
  • C3b is sporadically deposited onto surface of microbe
  • Recruitment of additional factor B results in formation of the C3 convertase C3bBb
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15
Q

What do both C3 convertases do

A
  • 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
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16
Q

What happens if C5b is deposited on microbial surface

A

Recruits C6, C7, C8 and C9 which form the Membrane Attack Complex (MAC)

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17
Q

How do bacteria evade complement opsonisation

A

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

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18
Q

How are neutrophils primed or activated

A

Pathogen recognition receptors which detect microbes or microbial products

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19
Q

What 3 different types of PRRs exist

A

TLR- toll like receptors that detect conserved microbial structures
CLEC- c type lectin detect microbial carbohydrate
FPR- Formylated peptide receptors which detect formylated peptides

20
Q

How can neutrophils indirectly detect bacteria

A

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

21
Q

What are the 4 different classes immune receptors that modulate function?

A

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

22
Q

Why do some receptors have both activating and inhibitory members

A

Fine tune immune responses

23
Q

How is chemotaxis inhibited

A

CHIPs bind to C5aR and FPR1 preventing binding of C5a and fMLP

24
Q

How is phagocytosis inhibited

A
  • 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
25
Q

Kill neutrophils

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

26
Q

Inhibit activating receptors

A

S. aureus expresses molecules at surface which bind to activating receptors and blocks their function

27
Q

Activate inhibitory receptors

A

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

28
Q

Inhibit effect of anti microbial

A

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

29
Q

Manipulate intracellular signalling

A

Used by intracellular bacterial pathogens

30
Q

Modify bacterial surface

A

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

31
Q

What are the roles of antibodies against viruses

A

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

32
Q

Role of antibodies IgM,IgG,IgA

A
  • 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.
33
Q

How do viruses escape antibody recognition

A
  • 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.
34
Q

Interferons

A

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

35
Q

Different types of IFN

A

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.

36
Q

How do viruses combat IFN

A

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

37
Q

How do viruses fight back against T cells

A
  1. HIV kills CD4 T cells and alters macrophage function.
  2. Herpes simplex virus can prevent CD8 T-cell killing
38
Q

How do NK cells protect against viruses

A

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
39
Q

How do macrophages protect against viruses

A
  • Macrophages filter viral particles from blood.
  • Macrophages inactivate opsonized virus particles.
  • Macrophages present antigen to CD4 T cells.
40
Q

How do dendritic cells protect against viruses

A
  • 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.
41
Q

What recepto do neutrophils express when selections bind to endothelial cells

A

PSGL-1

42
Q

How do s aureus evade antibody response

A

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

43
Q

What bacterial endotoxins does the alternative pathway recognize

A

Lipopolysaccahrides
Gram negative bacteria outer membrane

44
Q

Factor H

A

Inhibits C3 convertases

45
Q

Factor B and D

A

Involved in alternative pathway
Leads to C3b formation

46
Q

How do T cells affect viral infection

A

They control enveloped and noncytolytic viral infection
T cells recognize viral peptides eg linear epitopes (from glycoproteins or nucleoproteins) on MHC

47
Q

When is Cd4 TH2 responses detrimental

A

If they prematurely limit Th1 inflammatory and cytolytic responses