PATHOGEN ASSOCIATED MOLECULAR PATTERNS AND ITS INVOLVEMENT IN THE INNATE IMMUNE RESPONSE

By: Rebecca D. Riggs

INNATE IMMUNITY

The initial, immediate response to an invading organism by the host.

2 Major Types of Innate Response: Inflammation Antiviral Defense

Innate immune system is triggered by many invading molecules and we will discuss Pathogen-Associated Molecular Patterns (PAMPs) in detail

INNATE IMMUNITY There are many types of pattern recognition

receptors in different locations in tissues that respond to invading organisms

Recognition molecules are expressed by: Phagocytes, mainly Macrophages and Neutrophils Dendritic cells Other cells

Receptors can be found on the plasma membrane or endosomal membranes and in the cytoplasm of cells Attacks bacteria outside cells as well as within cellular

compartments Upon detection of the microbe or a damaged cell

Will Ingest and Destroy Initiate Inflammatory Response Activate Adaptive Immunity

PHAGOCYTES

First line of defense against invading pathogens

2 Major Functions: Ingest and Kill Bacteria Increase antimicrobial activity of the pathogen at

the site of initial infection

Polymorphonuclear Leukocytes AKA Neutrophils Majority of White Blood Cells that circulate and

initiate inflammatory response

MACROPHAGES

Macrophages are Monocytes until Activated by an Antigen

Names vary depending on tissue location Kuppfer Cells in the Liver Microglial Cells in Central Nervous System Osteoclasts in the Bone

Kill Bacteria by creating Reactive Oxygen & Nitrogen Species that are toxic to microorganisms

Secrete Cytokines that bind to Signaling Receptors on other cells to enhance host response Act on endothelial cells to recruit more monocytes to

the site of infection

CYTOKINES

Cytokines will initiate various Cellular Responses depending on the type of Cytokine and its target location.

CYTOKINES

DENDRITIC CELLS

Antigen presenting cells Present Antigen to Naïve T Cell Naïve T Cell Differentiates into Effector T cells

Derived from bone marrow cells Present in skin and most tissues Most versatile PAMP recognition cell because of

the number of receptors both internal and external

TLR signaling leads to Cytokine and costimulatory molecule production

TYPES OF PAMPS

Lipopolysaccharide layer of Gram (-) Microorganisms

Lipotechoic Acid and Peptidoglycan of Gram (+) Microorganisms

Flagellin DNA and RNA from

bacteria and viruses

MORE EXAMPLES OF PAMPS

PATHWAY ACTIVATION

PAMP binds to a TLR to activate cell signaling

TYPES OF TOLL LIKE RECEPTORS (TLR)

9 functional TLR’s Found on cell surface and

intracellular membranes TLR-1, 2, 4, 5, 6 are located

on the plasma membrane and recognize PAMPs

TLR-3, 7, 8, 9 are located inside the cell, on endosomes and recognize nucleic acid ligands from both bacteria and viruses

SPECIFICITY OF TLRS CAN BE INFLUENCED BY NON-TLR MOLECULES

TLR4 response to LPS LPS binds to soluble LPS-binding protein in blood

or extracellular fluid Protein MD2 bind to Lipid A of LPS Complex promotes binding to receptor

OVERVIEW OF THE PAMP SIGNALLING CASCADE

PATHWAYS INITIATED BY TLR’S

MAP KINASE CASCADE

JNK SIGNALING PATHWAY

APOPTOSIS

The TNF-R can activate caspase 8 to initiate the extrinsic pathway of apoptosis

P38 PATHWAY

Mammalian p38s are activated by extracellular stimuli: UV, Heat, Inflammatory Cytokines (TNF- & IL-1) other Growth Factors

Many Receptor Mechanisms Toll-Like Receptors activated by LPS to induce apoptosis

Dependent upon stimuli and on the cell type. Insulin Stimulates p38 in 3T3-L1 adipocytes but

downregulates p38 activity in chick neuron cells. Activated by Map Kinase Kinase, specifically MKK3

and MKK6 Controls apoptosis and the release of cytokines by

macrophages and neutrophils as well as other cellular responses

P38

P38

Apoptosis Known to occur consecutively with activation of p38

pathway Dependent upon cell type. Can promote cell death in

some cells while others it enhances survival, growth, and differentiation.

Inflammation Activates production of inflammatory cytokines Production of enzymes involved in connective tissue

restructuring (COX2) Expression of intracellular enzymes (iNOS) which

regulates oxidation

P38 AND JNK

Often Co-activated due to overexpression of MAP3Ks

Pathways are turned off by MAP Kinase Phosphatases

RESOURCES

Zarubin, T. HAN, J. Activation and signaling of the p38 MAP kinase pathway. Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA http://www.nature.com/cr/journal/v15/n1/full/7290257a.html