Pattern Recognition Receptors and Cytokines

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Western University
Microbiology and Immunology
Microbiology and Immunology 3300B
Rodney Dekoter

LECTURE 4: PATTERN RECOGNITION RECEPTORS AND CYTOKINES Lecture 4 Learning Objectives 1. Learn the major Pathogen Associated Molecular Patterns (PAMPs) and the Pattern Recognition Receptors (PRRs) that identify them 2. Learn the major cytokines and chemokines 3. Understand the basic intracellular signaling mechanisms of the PRR, cytokine and chemokine receptors Adaptive VS. Innate Receptors Pathogen-Associated Molecular Patterns (PAMPs)  Molecules found only in pathogens  Individual PAMPs will be present on a broad range of pathogens  Evolutionarily conserved Common Bacterial PAMPs  A lot of the PAMPs that we detect are found in the cell wall  Human DNA – methylation of cytosines o Bacteria DNA differs as their cytosines are not methylated  CpG DNA – DNA bases are held together by phosphodiester bonds which is what the p stands for  Flagellin – highly conserved evolutionarily, and thus act as PAMPs  Metabolites Viral PAMPs  Viruses have PAMPs associated with them as well  Associated with viral genomes  Some viruses are double stranded RNA, are interpreted as foreign as our RNA is mostly single-stranded  Gain entry into our cells through the endosomal pathway, but our DNA is in the nucleus and RNA is in the nucleus/cytoplasm – so our bodies detect DNA found in the endosomal pathway as something foreign Pattern Recognition Receptors (PRRs)  Receptors that bind to PAMPs  Germ-line encoded  2 major types: o Toll-like receptors (TLRs) o Non-TLRs  A fly missing toll o Investigated by geneticists o Kept toll operational o Investigation showed that fungus had grown inside the fly o Flies do not have adaptive immune systems, innate immune system only Toll-Like Receptors (TLRs)  Critical in certain parts of innate detection machinery in our bodies  They detect a large number of PAMPs  Combinations of TLR-2, TLR-6, and TLR-1 detect lipopeptides  TLR-5 detect flagellin  TLR-4 detect LPS Should know table but do not consider cellular distribution Receptor Signaling – TLRs  Pathway is universal for most of the TLRs  When TLRs are not active, they exist as monomers on the surface  Dimerization produces active TLRs  Dimerized TLRs recruit two proteins which together form ubiquitin ligase – combine and transfer ubiquitin to proteins  Now an active receptor capable of inducing signaling  Attaches ubiquitin to itself as well as NEMO which is a complex of proteins  TAK1 is phosphorylated and binds to NEMO which associates with IKK and phosphorylates IKKB  Targeted for degradation Not all TLRs are the Same  Virus-recognizing TLRs: o Use TRIF or MyD88 without Mal  Absence of Mal = No IRAK signaling  No IRAK = no NFB o IRF3 or IRF7 activated  Induce interferon genes  Drive anti-viral responses  Study hint: o IRF3 is downstream of TLR3 o IRF7 is downstream of TLR7 NODs – “Intracellular TLRs”  Dimerize when ligands are encountered  Recruit RIPK2
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