4. innate sensing of pathogens

microbial non-self

• recognition of molecules ONLY present in microbes

• macrophages, dendritic cells, epithelial cells

missing self

• recognition of cells NOT expressing “self” molecule

• natural killer cells

characteristics of pathogen associated molecular patterns (PAMPs)

• important for recognition of microbial non-self

• gene products unique to microbes → molecular signatures of microbial invaders

• conserved among microbes of a given class → broad detection ability

• essential for microbial survival

• ex. LPS (gram -); peptidoglycan (gram +)

damage-associated molecular patterns (DAMPs)

• molecules that are released from damaged or necrotic cells

• stimulate elimination of damaged cells and initiate tissue repair

pattern recognition receptors (PRRs)

• recognize PAMPs and DAMPs

• receptors expressed on macrophages, dendritic cells, lymphocytes, epithelial/endothelial cells

• signal to induce inflammatory cytokines & activate host defense mechanisms

what are the 5 families of PRRs?

1. toll-like receptors (TLRs)

2. C-type lectin receptors (CLRs)

3. NOD-like receptors (NLRs)

4. RIG-like receptors (RLRs)

5. cytosolic DNA sensors (CDSs)

what does TLR-2 bind to?

peptidoglycan → gram + bacteria

what does TLR-4 bind to?

LPS → gram - bacteria

what do TLR-3, -7, -8 bind to?

viral RNA

what does TLR-9 bind to?

• bacterial DNA → unmethylated cytosine-guanine sequence/motifs (CpGs)

  • less cytosine methylation in bacterial genome than mammalian genome

what are the two signal pathways following TLR activation?

1. inflammatory pathway

   • NF-κB → acute inflammation & stimulation of adaptive immunity

2. anti-viral defense

   • interferon regulatory factors → production of type-1 interferons → antiviral state

what do NOD1 and NOD2 bind to?

peptidoglycan in the cytosol

NLRP3

• expressed in macrophages, neutrophils, keratinocytes, and other cells

• detects PAMPs (bacteria)

• detects DAMPS → extracellular ATP, uric acid crystals from nucleic acids, etc.

  • urate, cholesterol crystals

what is the role of caspase-1 in the inflammasome?

cleaves pro-IL1β → active IL-1β (pro-inflammatory cytokine)

how can pathogens resist/evade innate immune system?

• prevent phagolysosome formation

• escape phagosome into the cytoplasm

• capsule inhibits phagocytosis

• production of catalase → breaks down reactive oxygen intermediates