Quiz 2: Chapters 2 and 3

Toll-Like Receptors (TLR)

transmembrane proteins on cell surface and endosomes; different members recognize a variety of PAMPs like some bacterial proteins

TLR Lipopolysaccharide

gram-negative bacteria

TLR Lipoteichoic Acid

gram-positive bacteria

TLR ss and dsRNA

viruses

Lectin Receptor

bind carbohydrates common to pathogen cell surfaces, binding activates phagocytosis

Lectin Receptor CD206

recognizes sulfated sugars, polysaccharides with terminal mannose, fucose, or N-acetylglucosamine

Scavenger Receptor

SR-A and SR-B on macrophages, bind negatively charged ligands, binding activates phagocytosis

Scavenger Receptor Negative Ligands

sulfated sugars, lipoteichoic acid, lipopolysachharide

Cytosolic Innate Receptor

recognizes intracellular cytosolic PAMPs like viral nucleic acids and bacterial signaling molecules; activate cellular responses that inhibit growth of intracellular pathogens, recruit white blood cells to destroy infected host cells

Cytosolic Innate Receptor: RIG-1

recognizes viral RNA

Cytosolic Innate Receptor: NLRs

NOD-like receptors, recognize bacterial cell wall components in the cytosol

Toll-Interleukin Receptor (TIR)

cytosolic signaling domain

TLRs That Recognize Bacterial PAMPs

activate transcription factor NFkb via a signaling pathway that starts with MyD88

TLRs that Recognize Nucleic Acid PAMPs

activate transcription factors IRF3 and IRF7 via a signaling pathway that involves TRIF and TRAM

TRIF

Toll-Receptor Associated Activator of Interferon

TRAM

Toll-Receptor Associated Molecule

TLR4 Signaling Pathway Result

with IkB degraded, NFkB moves from the cytosol to the nucleus; activates transcription of genes involved in inflammation

TLR Bacterial PAMP Pathway Result

causes destruction of IkB to free NFkB to enter the nucleus and transcribe genes for cytokines IL-1 and TNF-α

TLR Signaling To Produce Interferons Pathway Result

when phosphorylated, IRF3 and IRF7 activate genes involved in defense against viral infections, including the genes that encode interferons

TLR that Bind Viral Nucleic Acids Pathway Result

phosphorylated IRF3 and IRF7 enter nucleus to transcribe interferons and other genes that promote defense against viral infections

TLR4

ligand: LPS

expressing cells: macrophages, neutrophils, dendritic cells, mast cells, B cells

TLR3

Ligand: double stranded (ds) RNA

Expressing Cells: dendritic cells, B cells

TLR7

Ligand: single stranded RNA

Expressing Cells: macrophages, mast cells, B cells

β-glucan

a type of lectin receptor; bind carbohydrates to cell surface; binding activates phagocytosis

Cytokines

secreted proteins that have signaling roles in the immune response

Inflammatory Cytokines

induce TNF-a and IL-1; causes swelling and fluid accumulation; dilate blood vessels and increase vascular permeability; induces local blood vessels to express cell surface proteins that bind and recruit immune cells

Chemokines

type of cytokine that act as chemoattractants for immune cells; attract immune cells to site of infection and inflammation to better fight infections

IL-1

secreting cells: macrophages, dendritic cells, fibroblasts

function: inflammation, acute-phase response

IL-6

secreting cells: dendritic cells; induces fever and activates liver cells to produce acute phase response proteins (MBL and C-reactive protein)

TNF-a

secreting cells: macrophages, function: inflammation, acute-phase response; induce fever and increase vascular permeability

INF-a/INF-B

Secreting cells: macrophages and virally infected cells

Function: activation of NK cells, prevents viral replication

CXCL8

chemokine that attracts neutrophils and basophils

Neutrophil Migration/Recruitment Steps

rolling adhesion via weak interaction between neutrophil glycoproteins and selectins on endothelial cells; tight binding of neutrophil integrin LFA-1 to ICAM-1 in response to CXCL8; diapedesis; migration

Diapedesis

neutrophils cross the endothelial cell layer

Migration

chemotaxis of neutrophils towards source of CXCL8

Alternative Pathway Simple

spontaneous, first to act

Lectin Pathway Simple

second to act, activated by recognition of bacterial oligosaccharides ending in mannose, fucose

Classical Pathway Simple

third to act, best activated by antibodies bound to pathogen surface

C3a

small soluble peptide; recruitment of phagocytes, granulocyte activation

C3b

attaches to pathogen surface; pathogen opsonization, pathogen lysis

Alternative C3 Convertase

cleaves more C3 to form C3b that covalently attaches to pathogen surface to react with factors B and D to form more alternative convertase

Mannose Binding Lectin (MBL)

binds to mannose on pathogen cell surfaces; MBL hexamer complexes with proteases MASP-1 and MASP-2; acts an opsonin

C-reactive proteins

on pathogen surface; binds C1q hexamer complexed with proteases C1R and C1s; acts as opsonin

Classical C3 Convertase

formed by MBL and C-reactive protein initiating parallel and homologous pathways; MBL binding activates MASP-1 and MASP-2; C1q binding to CRP or immunoglobulin complexes activates associated C1r and C1s

Anaphylatoxins (C3a, C5a)

induce degranulation of mast cells and basophils, act as chemoattractants for phagocytes, increase expression of complement receptors and phagocytes

Opsonin

C3b binds to complement receptor CR1 on macrophage, iC3B bind to complement receptor CR3 and CR4 on macrophage; stimulates phagocytosis

MAC (Membrane Attack Complex)

C3bBb recruits another molecule of C3b to form C3b2Bb; alternative C5 convertase

Alternative C5 Convertase

cleaves C5 to C5a and C5b, C5b associates with C6 and C7; exposed hydrophobic region of C7 allows association of C5b67 with pathogen membrane; addition of C8 nucleates polymerization of C9 molecules in target cell membrane to form a pore

Properdin

Factor P, accelerator, stabilizes alternative pathway C3 convertase (C3bBb) on pathogen cell surfaces

Factor H

brake, binds to C3b; promotes cleavage of C3B by factor 1 to form inactive iC3b, binds preferentially to host cell membranes via interaction with sialic acid

DAF (Decay Accelerating Factor)

inactivates C3bBb by promoting dissociation of Bb from C3b

MCP (Membrane Cofactor Protein)

binds to C3bBb and promotes both dissociation of Bb and cleavage of remaining C3b by factor 1 to form inactive iC3b

Pathogen Proteases

aid in tissue breakdown and invasion; cleave C4 to C4a and C4b in lectin and classical pathways, C4b attaches to cell surface by thioester bond like C3b; also cleaves C2 to C2a and C2b

a2-macroglobulins

protease attack exposes internal thioester that bonds with protease; undergoes shape change to enclose proteins and prevent access to other substrates