Immunology - Lecture 1 - Introduction to Innate Immunity 3 Why are these systems so complex? · Pathogens: * Rapid generation time * Huge effective populations * Rapid mutation rate · Vertebrate hosts (relatively) # Slow generation time Small effective populations * Slow mutation rate · All organisms have innate defences which are complex and diverse driven by exposure to equally diverse evolving pathogens # Pathogens and host locked in an evolutionary molecular arms race * Key = diversity Many solutions to this problem * Co-evolution is critical # Pathogen may become more or less virulent to balance replication with spread host to host · Many ways to generate diversity: Cyclostomes: variable lymphocyte receptors (VLRs) * Echinoderms: TLRs * Molluscs: fibrinogen-related proteins (FREPs) * Insects: Down syndrome cell adhesion molecule (DSCAM) > Immune evasion mechanisms: . Pathogens use their own counter-measures to block host immunity . This induces greater complexity over time . Results in co-evolutionary balance of host-pathogen interactions · Viruses commonly target PRR signalling
Sequestration of dsRNA VACV, reoviruses, HSV, CMV, influenza A viruses, EBOV, EBV Degradation of dsRNA BVDV Inhibition of mda-5 Paramyxoviruses dsRNA - Extracellular/ endosomal mda-5 dsRNA TLR3 + TRIF Inhibition of TLR signalling HCV, VACV TAR2/3 5'-triphosphoRNA / RIG-I TRAF3 TRAF6NEMO IKKa TAK1 IKKB TANK etc IKK& TBK-1 Intracellular Inhibition of RIG-I Influenza A viruses Degradation of Cardif HCV IRF-7 1 IxBa IRF-3 NF-KB Cytoplasm IRF-3 p38 IRF-7 Inhibition or induced loss/degradation of IRF-3 RABV, HTNV, HHV-6/8, rotaviruses, BVDV, CSFV, HPV16, HSV, THOV, RSV ATF-2/ c-Jun PRD IV Nucleus IRF-3CBP/p300 NF-KB PRD I/III PRD II IFN-ß promoter Inhibition of IKK complex HPV, VACV, HCV, AdV Inhibition of VAK BDV, VACV Ba Inhibition of NF-KB ASFV, VACV, MYXV TATA · Streptococcus evades complement, phagocytosis and chemotaxis using CHIPS and eap proteins * CHIPS block C5a receptor