P ATHOGEN A SSOCIATED M OLECULAR P ATTERNS AND ITS INVOLVEMENT IN THE I NNATE I MMUNE R ESPONSE By: Rebecca D. Riggs

I NNATE I MMUNITY 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

I NNATE I MMUNITY 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

P HAGOCYTES 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

M ACROPHAGES 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

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

CYTOKINES

D ENDRITIC C ELLS 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

T YPES OF PAMP S Lipopolysaccharide layer of Gram (-) Microorganisms Lipotechoic Acid and Peptidoglycan of Gram (+) Microorganisms Flagellin DNA and RNA from bacteria and viruses

M ORE E XAMPLES OF PAMP S

P ATHWAY A CTIVATION PAMP binds to a TLR to activate cell signaling

T YPES OF T OLL L IKE R ECEPTORS (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

O VERVIEW OF THE PAMP SIGNALLING C ASCADE

P ATHWAYS I NITIATED 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 P ATHWAY 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

P 38

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

R ESOURCES Zarubin, T. HAN, J. Activation and signaling of the p38 MAP kinase pathway. Department of Immunology, The Scripps Research Institute, N. Torrey Pines Road, La Jolla, CA, 92037, USA a.html a.html