Identification of Microbes

Transcription

1 Identification of Microbes Recognition by PRR (pattern recognition receptors) Recognize conserved molecular patterns on microbes called pathogen associated molecular patterns (PAMPs) which are not present on the host. PAMPs include LPS, Peptidoglycan, Lipoarabinomannans, dsrna, b-glycans

2 3 Classes of PRRs 1. PRRs that signal an infection >Include TLR(Toll like receptor family) >Expressed external or internally >Activation of inflammatory signaling pathways >Inflammatory cytokines (TNF-alpa, IL-8, IL-1) >Regulate activation of adaptive immune response 2. Phagocytic PRRs Expressed on the surface of phagocytic cells Mediate uptake of microbe into phagocytes 3. Secreted PRRs accessory proteins for PAMP (Pathogen-associated molecular patterns ) recognition

3 1. PRRs that signal an infection Toll-like receptor(tlr) NOD-like receptor(nlr) >> Inflammasome RIG-I-like receptor (RLR)

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6 TLR3 ECD

7 TLR3 ECD +dsrna Science 2008

8 Heterodimer + lipopeptide

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10 Structure of TLR Transmembrane-protein -Cytosolic side: -Extracellular: TIR-domain conserved stretch of ~200 amino acids LRR-domain specific pathogenreceptors

11 There are 10 TLR s active in mammalian immune-system Receptor (Pattern Recognition Receptors) TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR9 TLR 8,(10) Agonist(s) (Pathogen-Associated Molecular Patterns) Heterodimerizes with TLR2 Bacterial lipopeptide PGN, some LPS, some LTA, lipoproteins Viral or Bacterial dsrna Gram(-) LPS, Taxol, some LTA Flagellin Heterodimerizes with TLR2 Imidazoquinoline Bacterial DS DNA (CpG) viral SS RNA, (Unknown)

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14 NOD receptor NOD proteins or nucleotide-binding oligomerization domain Recognize intracellular peptidoglycan-derived PAMPs and transduce signals three distinct functional domains carboxy-terminal ligand-recognition domain (LRD) centrally located NOD amino-terminal effector-binding domain (EBD) CARD domains in mammals Interacts and activates RIP2 inducing NFkB and MAPkinase pathways

15 Numerous innate sensors of bacterial peptidoglycan Mammalian NOD1 and NOD2 (intracytoplasmic sensors) Seen by Tlr2 (cell surface receptor) Recognize intracellular peptidoglycanderived PAMPs Lysozyme (in serum and secretions) clips here

16 NOD signaling activates NFkB transcription factor Peptidoglycan

17 NOD Proteins

18 NOD like receptor (inflammasome)

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20 RIG-I-like receptor (RLR) Cytoplasmic RNA helicase >> critical for the host antiviral responses Sense double stranded RNA

21 Inflammatory Response

22 3 Classes of PRRs 1. PRRs that signal an infection >Include TLR(Toll like receptor family) >Expressed external or internally >Activation of inflammatory signaling pathways >Inflammatory cytokines (TNF-alpa, IL-8, IL-1) >Regulate activation of adaptive immune response 2. Phagocytic PRRs Expressed on the surface of phagocytic cells Mediate uptake of microbe into phagocytes 3. Secreted PRRs accessory proteins for PAMP recognition

23 2. Phagocytic PRRs Bind Carbohydrates 1. Macrophage Mannose Receptor (C-type lectin) Recognizes patterns of mannose residues in a certain spatial orientation unique to microbes Only found on macrophages (not monocytes or neutrophile) 2. Glucan Receptor (Dectin-1) - Recognizes b-1,3 & b-1,6 linked glycans Present on all phagocytes

24 3. Secreted PRRs activate the Complement (C ) System (13 장 ) Complement for antibody function Important proteins (about 20) in Blood serum Complement system is activated by innate immunity Recognition by Complement receptors (CR) CR1, CR2, CR3, CR4, C5a, C3a Comprised of plasma proteins that when activated forms a triggered enzyme cascade Zymogens activated by the cleavage of other proteases Precursor enzymes Function Facilitates the uptake & destruction of pathogens by phagocytes Induces an inflammatory responses

25 Activation of C System C4b + C2 C3b + Bb

26 3 pathways

27 1 Major functions of complement 2 3 For inducing inflammation

28 Major functions of complement Viral neutralization