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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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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


  • 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


Vector: Reduviid bugs (Triatoma & Rhodnius)

a.k.a. Kissing bug


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.


Tlr roles
TLR Roles

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


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


Activation of adaptive immunity by innate immunity
Activation of adaptive immunity by innate immunity System”. Scientific American, Jan (2005), 38-45.

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


Hemozoin: A Malarial Metabolic Waste System”. Scientific American, Jan (2005), 38-45.

PfHZ

sPLHZ

Rapid crystalline (0.7-0.9 mm)

Size and Shape similar to PfHZ

(see Inset). Bar size is 200 nm.


Intracellular microbial sensors
Intracellular Microbial Sensors System”. Scientific American, Jan (2005), 38-45.

  • 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)


Card domain
CARD domain System”. Scientific American, Jan (2005), 38-45.

  • CARD(Caspase-Activating and Recruitment Domain)

  • Found in some caspase proteins

  • Mediates protein-protein interaction


CARD System”. Scientific American, Jan (2005), 38-45.

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)


Nod protein structure

CARD System”. Scientific American, Jan (2005), 38-45.

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)


Nod ligands peptidoglycan
NOD ligands: Peptidoglycan System”. Scientific American, Jan (2005), 38-45.

  • 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)


Nod signalling

RIP2 System”. Scientific American, Jan (2005), 38-45.

RIP2

RIP2

IKK complex

IkB

IkB

NFkB

NFkB

Proteasome

NOD signalling

NOD2

PGN

NOD2

NOD1

NOD1

Transcription


Nod like receptors nlrs
NOD-Like Receptors (NLRs) System”. Scientific American, Jan (2005), 38-45.

  • 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


Nod 2 and crohn s disease
NOD-2 and Crohn’s disease System”. Scientific American, Jan (2005), 38-45.

  • 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


Nod like receptors rig and mda intracellular microbial sensors

Summary System”. Scientific American, Jan (2005), 38-45.

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


Anti-microbial Functions System”. Scientific American, Jan (2005), 38-45.of Phagocytic Cells

  • Upon Receptor-Mediated recognition

  • Phagocytosis and Internalization

  • Phagosome Biogenesis

  • Anti-Microbial Products

  • Pro-Inflammatory Response (last lecture)


Major Players System”. Scientific American, Jan (2005), 38-45.

  • 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


Underhill and Ozinsky. Annu. Rev. Immunol. 2002 System”. Scientific American, Jan (2005), 38-45.


Formation of the phagolysosome upon ingestion of a microbe
Formation of the phagolysosome System”. Scientific American, Jan (2005), 38-45.upon ingestion of a microbe


Phagosome maturation System”. Scientific American, Jan (2005), 38-45.

Cellular Microbiology, 1999, 1(3):195-203


Degradation in the phagolysosome
Degradation in the phagolysosome System”. Scientific American, Jan (2005), 38-45.

Phagolysosome

Lysosome

Acid hydrolases

Endosome

Bacteria degradation


Phagocytosis and Anti-Microbial Products System”. Scientific American, Jan (2005), 38-45.

Bacteria

Lysosomes

Plasma membrane

Phagolysosome

Phagosome

NAPDH

oxidase

O2-

Proteases

H2O2

Nitric Oxide

Ionic strength

pH


TNF- System”. Scientific American, Jan (2005), 38-45.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


NO System”. Scientific American, Jan (2005), 38-45.

NOS

Arginine

Citruline

RNS

iNOS


O System”. Scientific American, Jan (2005), 38-45.2

O2-

ROS

PKC

p40phox

PI3K

P

P

PKA

P

P

MAPK

Resting

Active

p22phox

gp91phox

Heme

FAD

NADPH

Rac

p47phox

P67phox


Reactions between ros and rns
Reactions Between ROS and RNS System”. Scientific American, Jan (2005), 38-45.

  • NO + O2- NO2 + ONOO-

NONOates

S-nitrothiols

Nitrite

Nitrous Acid


Chakravortty and Hensel. Microbes Infect. 2003. System”. Scientific American, Jan (2005), 38-45.


Formation of Oxylipins disrupts membrane System”. Scientific American, Jan (2005), 38-45.

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


Evasion

Evasion: System”. Scientific American, Jan (2005), 38-45.

“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


Bacterial defense against phagocytes
Bacterial defense against phagocytes System”. Scientific American, Jan (2005), 38-45.

Green:host

Orange:bacterial

 √ Induction of apoptosis X Uptake

√ Down-regulate 

√ Escape 

X Endosomal trafficking/ Phagosome maturation 

X Defense factors 


EVASION MECHANISMS System”. Scientific American, Jan (2005), 38-45.


Streptococcus suis System”. Scientific American, Jan (2005), 38-45. type 2

Wild type S735

Mutant 2A

Phagocytosis

resistance

Phagocytosis

sensitive

Adapted from Charland et al.,1998

MS150502 3


Host Signalling Alteration System”. Scientific American, Jan (2005), 38-45.

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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