lecture 18: molecular innate immunity

pattern recognition receptors (PPR)

soluble, cell-associated receptors that mainly bind to carbohydrates or nucleic acid

Toll-like receptors (TLRs) (PPR)

• PAMP binds to a TLR, forcing 2 TLR proteins to dimerise and create a docking platform for internal helper proteins

• this recruits adapter proteins to trigger a kinase cascade to activate transcription factors like NF-kB and IRFs

C-type lectin receptors (CTLRs) (PPR)

calcium-dependent carbohydrate recognition domain on the outside of the cell, important in fungal immunity

NOD-like receptors (NLRs) (PPR)

• under normal conditions, the NLR is auto-inhibited so it does not accidently trigger

• when the C-terminus sensor binds to its target, it unfolds and oligomerises to expose the N-terminus so it can interact with downstream signaling molecules

RIG-I-like receptors (RLRs) (PPR)

detects viral dsDNA, binding causes it to interact with mitochondrial signalling proteins, triggering the production of type I interferons to block viral replication

cytosolic DNA sensors (e.g. cGAS-STING) (PPR)

cGAS binds to foreign dsDNA and synthesises cGAMP. it travels to the membrane of the ER and binds to a receptor, STING, which recruits TBK1 to activate transcription factors like NF-kB and IRF-3

danger-associated molecular patterns (DAMP)

another type of cytosolic DNA sensor

necrotic cells release…

HMGB1, HSP60 and cytokines

the combined activation of different PRRs, DAMP and communication within the immune system informs about:

• what sort of pathogen

• the level of threat

• whether its chronic, new or recurring threat

cytokines

• short-range communication → autocrine and paracrine

• broad-acting

• specific-acting

chemokines

• attractant/ movement so that that the immune cells go into tissues

recruitment of inflammatory cells

• when the complement system encounters an invader, it splits proteins to create c5a and c3a, which acts as chemoattractants

• neutrophils and mast cells have c5a receptors, which when bound, guides them to the infection site to release inflammatory mediators

what can S.aureus chemotaxis do

block the c5a receptor

opsonisation

• c3b physically coats the bacteria

• phagocytes have c3b receptors to increase binding and phagocytosis (important for killing gram-positive bacteria

how can S.pneumonia and N. meningites evade phagocytes?

due to their thick capsules

cell lysis (c5b-c9)

c9 polymerises to form hollow cylinders, creating pores in the bacterial membrane (important defence against gram-negative bacteria)

what can a phagocyte do after engulfing an agent?

1. the cell undergoes a respiratory burst, using oxygen to manufacture toxic chemicals to dissolve the invader

2. the cell manufactures NO gas which binds to the iron inside the bacterium’s metabolic engine

3. the cell dumps stored proteins onto the bacteria- including lysozymes and lactoferrin

what happens when a cell gets infected/becomes malignant

it downregulates MHC-1 to avoid being detected by killer T-cells

a macrophage synthesises IFN-alpha and IFN-beta, which binds to receptors on NK cells, secreting IFN-gamma, which can stimulate:

1. enhancement of microbial killing

2. enhanced target killing

3. enhanced antigen presentation to T-cells