p athogen a ssociated m olecular p atterns and its involvement in the i nnate i mmune r esponse by:...
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PATHOGEN ASSOCIATED MOLECULAR PATTERNS AND ITS INVOLVEMENT IN THE INNATE IMMUNE RESPONSE
By: Rebecca D. Riggs
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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
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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
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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
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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
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CYTOKINES
Cytokines will initiate various Cellular Responses depending on the type of Cytokine and its target location.
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CYTOKINES
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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
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TYPES OF PAMPS
Lipopolysaccharide layer of Gram (-) Microorganisms
Lipotechoic Acid and Peptidoglycan of Gram (+) Microorganisms
Flagellin DNA and RNA from
bacteria and viruses
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MORE EXAMPLES OF PAMPS
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PATHWAY ACTIVATION
PAMP binds to a TLR to activate cell signaling
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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
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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
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OVERVIEW OF THE PAMP SIGNALLING CASCADE
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PATHWAYS INITIATED BY TLR’S
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MAP KINASE CASCADE
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JNK SIGNALING PATHWAY
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APOPTOSIS
The TNF-R can activate caspase 8 to initiate the extrinsic pathway of apoptosis
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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
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P38
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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
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P38 AND JNK
Often Co-activated due to overexpression of MAP3Ks
Pathways are turned off by MAP Kinase Phosphatases
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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