detecting and responding the pathogens Flashcards

1
Q

Describe innate immunity

A
  • rapid host defence against invading pathogens- within minutes
  • does not change - born w it
    -no requirement for memory
  • recognition of invading pathogens + activation of anti microbial response
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2
Q

what are the 4 steps of handling pathogens that are viruses?

A
  1. endocytosis
  2. cellular shut down
  3. self sacrifice
  4. cellular resistance
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3
Q

what molecular patterns can the innate immune system recognise?

A
  1. Highly conserved structures expressed by large groups of pathogens.
  2. Common biologic consequences of infection.
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4
Q

what does PAMPs stand for?

A

Pathogen associated molecular patterns
includes things like:
- bacteria
- virus
- parasite
- fungi

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5
Q

why is it important to recognise patterns?

A

To vastly expand the repertoire of ligands they can bind

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6
Q

what does DAMPs stand for?

A

Damage associated molecular patterns

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7
Q

what are DAMPs?

A

Endogenous molecules created to alert the host to tissue injury and initiate repair

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8
Q

name some examples of DAMPs

A

molecules
DNA
RNA
Extracellular ATP
Hyaluronic acid
Glucose
Fibrinogen
Fibronectin
Heat shock proteins
IL-1-a, IL-33

particles
Uric acid
Amyloid-b
Silica
Nanoparticles
Alum
Asbestos
Hemozoin

other
UVB
mutations

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9
Q

Why do we not recognise our own DNA and RNA and mount an innate response?

A

Our DNA and RNA is normally located where our pattern recognition receptors (PRRs) cannot access it

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10
Q

describe PRRs

A

Secreted and circulating receptors
Receptors on the cell surface and cell membranes
Receptors inside the cell (cytoplasmic)

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11
Q

What are cell associated PRRs

A

receptors that are present on the cell membrane or on organelles within the cytosol of cells
They are able to recognise a broad range of molecular patterns

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12
Q

what is the main family of cell associated PRRS

A

TLRs

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13
Q

how does TLR ( PAMPs) signalling work?

A

Different TLRs activate different signalling cascades depending on the pathogen being detected to tailor the immune response that is generated

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14
Q

give 3 examples of membrane bound PRRs

A

Mannose receptor - on macrophages (fungi)
Dectin-1 - widespread on phagocytes (beta glucans in fungal walls)
Scavenger receptors - on macrophages (wide variety of lipid-related ligands from pathogens or from host cells that are damaged, apoptotic or senescent

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15
Q

what are the three members that detect viral RNA in the cytoplasm?

A
  1. Retinoic acid-inducible gene I (RIG-I)
  2. Melanoma differentiated gene 5 (MDA-5)
    3.Laboratory of genetics and physiology 2 (LGP2)
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16
Q

describe Retinoic acid-inductible gene I ( RIG-I)

A
  • short dsRNA (up to 1 kb)
    • 5’ triphosphate (5’ppp) caps (ss or ds RNA)
    • e.g. influenza A and respiratory syncytial virus (RSV)
17
Q

Describe Melanoma differentiated gene 5 (MDA-5)

A

long dsRNA (over 2kb) with no end specificity
- replication intermediates
- e.g. rhinovirus (RV)

18
Q

describe Laboratory of genetics and physiology 2 (LGP2)

A

very high affinity for any dsRNA
- positive regulator of RIG-I and MDA5 signaling

19
Q

what are NOD- like Receptors involved in? ( NLRs)

A

-sensing cytoplasmic bacterial pathogens and DAMPS
-regulation of inflammatory & cell death responses

20
Q

how many NLRs genes are there in humans?

A

22

21
Q

How are NLRs characterised?

A

Characterised by the presence of a conserved nucleotide-binding and oligomerisation domain (NOD / aka NACHT)

22
Q

what are NLRs subdivided into?

A

4 subfamilies, based on N-terminal effector domains

23
Q

Why don’t NLRs activate interferons?

A

NLRs detect predominantly intracellular bacteria and IFNs are anti-viral cytokines

24
Q

what are NOD 1 & 2 activated by?

A

Activated by recognition of specific motifs (mostly muropeptides) present in bacterial peptidoglycan (PG)

25
Q

what does NOD 1 recognise?

A

meso-diaminopimelic acid (meso-DAP)-containing PGN fragments (mainly Gram-negative) in the periplasmic space

26
Q

what does NOD 2 sense?

A

muramyl dipeptide (MDP) a breakdown product of PG in the cell wall, found in the PGN of nearly all Gram-positive and Gram-negative organisms (also a major component of many immunoadjuvants)

27
Q

describe the NLR signalling path

A

Activation of the MAPK and NF-κB signalling pathways
Induction of pro-inflammatory cytokines and chemokines
Activation of antimicrobial functions
DO NOT activate IRF transcription factors

28
Q

what are high levels of DAMPs associated with?

A

many inflammatory and autoimmune diseases as well as atherosclerosis and cancer

29
Q

name harmful stimuli for the damage chain reaction

A

Pathogens
Injury
Heat
Autoantigens
Tumours
Necrotic cells

30
Q

what is the cytokine storm?

A

Profound increase in cytokines, chemokines & interferons

31
Q

what can a cytokine storm cause?

A

Causes severe inflammation and tissue damage

32
Q

what causes a cytokine storm?

A

genetic makeup of the host
persistence of the pathogen (evasion mechanisms)

33
Q

in sepsis, what does it mean if the pathogen isn’t cleared?

A

severe infection and dissemination to the circulation (bacteremia,viremia, or fungemia)

34
Q

what are the two main strategies of immunomodulation?

A
  1. Agonists- enhance TLR signalling
  2. Antagonists- inhibit TLR signalling
35
Q

what do Agonists do?

A

enhance TLR signalling

adjuvant effect (used with a primary treatment) promoting protective responses e.g. vaccines
immune stimulators
Modify adaptive immune response: bias Th and Treg responses
side-effects: potentially enhance inflammation

36
Q

what do antagonists do?

A

inhibit TLR signalling

block binding of ligands or protein-ligand complexes to receptors / interfere with intracellular adaptor molecules of common signalling pathways
sepsis syndromes, inflammation, arthritis, etc
side-effects: potentially allow pathogen outgrowth, mutation, etc