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Host-Pathogen Interaction

Host-Pathogen Interaction. Sites of microbial infection. Mouth. Conjunctiva of eye. Skin. Scratch, injury. Pores, hair Follicles, Sweat glands. Lung. Insect bite. Digestive tract. Urogenital tract. Pathogenic microbes. Normal non-pathogenic microflora. Anus.

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Host-Pathogen Interaction

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  1. Host-Pathogen Interaction

  2. Sites of microbial infection Mouth Conjunctiva of eye Skin Scratch, injury Pores, hair Follicles, Sweat glands Lung Insect bite Digestive tract Urogenital tract Pathogenic microbes Normal non-pathogenic microflora Anus

  3. Pathogens can be successful • in causing an infection • They can attach to and penetrate body surfaces Ex: Schistosoma mansoni • Pathogens can be introduced by a biting insect Ex: Malaria, Leishmania, virus, bacteria • Pathogens can take advantage of preliminarydamage (wound, respiratory tract damage) Ex: Trypanosoma cruzi

  4. Vector: Reduviid bugs (Triatoma & Rhodnius) a.k.a. Kissing bug

  5. However, the Immune Systemhas Natural, ConstitutiveMicrobial Sensors Utilized to Rapidly React to Invasive Pathogens.They are part of the Innate Immune Response and Play Pivotal Role in the Development of the Adaptive Immune Response.

  6. TLR Roles O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005), 38-45.

  7. O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005), 38-45.

  8. Activation of adaptive immunity by innate immunity dsRNA Unmethylated CpG DNA LPS Flagellin PGN Cytokines (IL-1, IL-6, IL-12, TNF) Chemokines (MIP-2, MIP-1a/b) Lipopeptides TLR4 TLR3 TLR5 TLR2 TLR9 TLR2 TLR1 Co-stimulatory molecules CD28 B.7 NF-kB TCR Phagocytic receptor Peptide MHC Naive T Cell Phagosome Microorganisms Antigen Presenting Cell

  9. Hemozoin: A Malarial Metabolic Waste PfHZ sPLHZ Rapid crystalline (0.7-0.9 mm) Size and Shape similar to PfHZ (see Inset). Bar size is 200 nm.

  10. Intracellular Microbial Sensors • Toll-like receptors: • Membrane Receptor that Sense Extracellular Microbes • and within phagosome/endosome. • NOD-Like Receptors, RIG and MDA: • Intracellular Microbial Sensors • Are Cytoplasmic surveillance proteins with CARD domain • NOD proteins(Nucleotide-binding oligomerisation domain) • Two members: NOD-1 and NOD-2 • RIG-1(Retinoid-induced gene 1) • MDA(Melanoma differentiation-associated gene)

  11. CARD domain • CARD(Caspase-Activating and Recruitment Domain) • Found in some caspase proteins • Mediates protein-protein interaction

  12. CARD Helicase domain CARD 1 925 RIG-I CARD CARD Helicase domain MDA-5/Helicard 1025 1 CARD 1 540 IPS-1/Cardif/VISA/MAVS *** *** *** *** Bouchier-Hayes L and Martin S.J., EMBO (2002)

  13. CARD NBD LRRs CARD CARD NBD LRRs NOD protein structure NOD-1 N-term C-term NOD-2 N-term C-term CARD (Caspase-activating and recruitment domain) NBD (Nucleotide binding Domain) LRRs (Leucine-Rich Repeats)

  14. NOD ligands: Peptidoglycan • Peptidoglycan (PGN) • Major component of gram+ cell wall • Found in thin layer in periplasmic space of gram– • Glycan chains alternating GlcNAc and MurNAc • linked by peptide bridge MDP Meso-DAP Philpott D.J. and Girardin S.E., Mol Imm (2004)

  15. RIP2 RIP2 RIP2 IKK complex IkB IkB NFkB NFkB Proteasome NOD signalling NOD2 PGN NOD2 NOD1 NOD1 Transcription

  16. NOD-Like Receptors (NLRs) • NOD1/2 IPAF/NAIP NALP3/ASC • Bacteria • PGN PGN • DAP (meso-diaminopimelic) • MDP (muramyl dipeptide) MDP • SalmonellaFrancisella • Legionella RNA (PAMP) • Flagellin Toxins • Danger-Associated Host Components • Uric Acid Crystals • Hemozoin ??? • (metabolic waste) NOD-1 NOD-2 Meylan et al. Nature July 2006

  17. NOD-2 and Crohn’s disease • Abnormal NOD-2 expression correlates • with defective epithelial defense • NOD-2 expressed in Paneth cells of intestine • Enteric bacteria induce a-defensin through NOD-2 to kill luminal microbes. • Clinical evidence: CD patients have decreased a-defensin expression in Paneth cells

  18. Summary NOD-Like Receptors, RIG and MDAIntracellular Microbial Sensors • That can detect bacterial and viral ligands • NOD detects PGN of several bacteria • Inflammatory response & Cell Death(IPAF/NAIP) • RIG-1/MDA-5 detects dsRNA of virus • Modulation of IFN signalling to control virus

  19. Anti-microbial Functions of Phagocytic Cells • Upon Receptor-Mediated recognition • Phagocytosis and Internalization • Phagosome Biogenesis • Anti-Microbial Products • Pro-Inflammatory Response (last lecture)

  20. Major Players • Polymorphonuclear leukocytes (PMNs) / neutrophils • Abundant, short lived • Elevated number indicate infection • Professional antigen presenting cells • Dendritic cells / Langerhan cells (skin) • Monocytes (blood)  macrophages (motile or stationary), which can be tissue specific • Longer lived, lower frequency

  21. Underhill and Ozinsky. Annu. Rev. Immunol. 2002

  22. Formation of the phagolysosomeupon ingestion of a microbe

  23. Phagosome maturation Cellular Microbiology, 1999, 1(3):195-203

  24. Degradation in the phagolysosome Phagolysosome Lysosome Acid hydrolases Endosome Bacteria degradation

  25. Phagocytosis and Anti-Microbial Products Bacteria Lysosomes Plasma membrane Phagolysosome Phagosome NAPDH oxidase O2- Proteases H2O2 Nitric Oxide Ionic strength pH

  26. TNF-a + TNF-R1 TNF-a + TNF-R1 IFN-a/b + JAK/TYK IL-1 + IL-1R1 LPS+TLR 4 NF-ΚB NF-ΚB IFN-g + JAK1/2 IFN-g + JAK1/2 STAT1 SAPs/JNKs MAPKs IL-6 + JAK1/2 ΚB STAT2 IKB IRF-9 p38 IRF-1 AP-1 NF-IL6 ISRE GAS NF-IL6 Induction of iNOS Expression AP-1 iNOS

  27. NO NOS Arginine Citruline RNS iNOS

  28. O2 O2- ROS PKC p40phox PI3K P P PKA P P MAPK Resting Active p22phox gp91phox Heme FAD NADPH Rac p47phox P67phox

  29. Reactions Between ROS and RNS • NO + O2- NO2 + ONOO- NONOates S-nitrothiols Nitrite Nitrous Acid

  30. Chakravortty and Hensel. Microbes Infect. 2003.

  31. Formation of Oxylipins disrupts membrane Deamination of nucleosides Abasic sites Strand breaks Oxidization and Nitrosylation of SH groups Nitrosylation of Tyrosine residues Inactivation of metal ions at active site Depletion of antioxidants Mechanisms of Microbicidal Activity • Polyunsaturated Lipids • DNA • Enzyme Function

  32. Evasion: “the act of physically escaping from something (an opponent or a pursuer or an unpleasant situation) by some adroit maneuver” Nature 3:11, 2002 editorial • Passive • Active

  33. Bacterial defense against phagocytes Green:host Orange:bacterial  √ Induction of apoptosis X Uptake √ Down-regulate  √ Escape  X Endosomal trafficking/ Phagosome maturation  X Defense factors 

  34. EVASION MECHANISMS

  35. Streptococcus suis type 2 Wild type S735 Mutant 2A Phagocytosis resistance Phagocytosis sensitive Adapted from Charland et al.,1998 MS150502 3

  36. Host Signalling Alteration Acid phosphatase Ca2+ Channel IFNg Ca2+Influx Tyrosine phosphatase JAK1 LPG [Ca2+]i (SHP-1) JAK2 PTK PKC Ser⁄Thr phosphatase PMA DAG STAT Protein phosphorylations PIP2 IP2 Ca2+ PLC G R FMLP INT EXT Ca2+stores Cellular functions • H2O2,O2- • IL-1 • phagocytosis • MHC Class II • c-fos expression M. Olivier 0295 2

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