The Innate Immune Response to Bacterial and Fungal Infections

The Innate Immune Responseto Bacterial and Fungal Infections

What Really Happens During the Lag Period

Before the Acquired Immune Response?

Innate immunity

Acquired immunity

Distinctions Between Innate and Adaptive Immunity

Innate immune system Adaptive immune system

Receptors Germline-encoded Somatically engineered

Distribution Non-clonal Clonal

Kinetics Rapid Slow (requires clonal expansion)

Specificity Recognizes non-self Recognizes “altered self” through “Pattern recognition” Primary structure (TCR)

Higher order structure (Immunoglobulin; BCR)

Effector Cells All Primarily lymphocytes, M

The Innate Immune Response is Conserved Throughout Evolution and is

Triggered by Pattern Recognition

Lipopolysaccharide is Composed of Lipid and Polysaccharide

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are needed to see this picture.

From: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)

The Complement System is Critical for Innate Immunity and is Triggered

by Multiple Ligands

Soluble “Defense Collagens”Participate in Innate Immunity

Pseudomonas aeruginosa

CRD (6 X 3)

Collagen domain

Domain Structure of Surfactant Protein A(SP-A), a Lung Soluble Defense Collagen (Collectin)

Alveolar macrophage

Phagocytosis is Mediated byReceptors of the Innate Immune System

and the Acquired Immune System

Examples of “Pattern Recognition Receptors” that Participate in Innate Immunity

Receptor Expression TargetReceptor Expression Target Ligand LigandIntegrinsIntegrins CR3 (CD11b/CD18; CR3 (CD11b/CD18; MM22) PMN, Mo, M) PMN, Mo, MYeast Yeast -glucan-glucan

C3bi, fibrinogen, LPS, ICAMC3bi, fibrinogen, LPS, ICAM11 Integrins Integrins Leuk Leuk YersiniaYersinia InvasinInvasin

33 Integrin (? Integrin (? vv3 3 )) M M Osteopontin Osteopontin

Scavenger ReceptorsScavenger Receptors SR-AI/SR-AIISR-AI/SR-AII MM Gram-positive bacteria Leipoteichoic acid Gram-positive bacteria Leipoteichoic acid

Gram-negative bacteriaGram-negative bacteria ?? MARCO MARCO MM E. coli, S. aureusE. coli, S. aureus ? ?Collectin ReceptorsCollectin Receptors C1qRC1qRp p PMN, Mo, MPMN, Mo, MC1q, SPA, MBLC1q, SPA, MBL

gp-340gp-340 MM SP-D, SP-A SP-D, SP-A SPR210SPR210 Mo, MMo, M SPA SPALectinsLectins Dectin-1 Dectin-1 MM, DC , DC YeastYeast -1,3-/ -1,3-/ -1,6 glucans -1,6 glucans CR3 (CD11b/CD18; CR3 (CD11b/CD18; MM22) PMN, Mo, M) PMN, Mo, MYeast Yeast -glucan-glucan

CD14CD14 Mo, MMo, M, soluble Gram-negative bacteria LPS, soluble Gram-negative bacteria LPS Gram-positive bacteria Gram-positive bacteria Peptidoglycan Peptidoglycan

Toll-like ReceptorsToll-like Receptors TLR2 TLR2 MM, imDC Gram-positive bacteria Peptidoglycan, Leipoteichoic acid, imDC Gram-positive bacteria Peptidoglycan, Leipoteichoic acid

MycobacteriaMycobacteria Lipoarabinomannan Lipoarabinomannan SpirochetesSpirochetes Lipoproteins, Lipopeptides Lipoproteins, Lipopeptides Mycoplasmas Mycoplasmas LipopeptidesLipopeptides

TLR4 TLR4 MM Gram-negative bacteria LPS Gram-negative bacteria LPS

C

C

SoS o

C

C

SoS o

CL

SRECLOX-1CD 68dSR-C ISR-B1CD 36MARCOSR-A II

NNNNNNN

N

N

N

N

N

C C

C C C

SR-A I

NNN

C C C

C CC

CC

C

C

*

*

SR-CSR-B

C

C C

N N N

SR-A

SR-A III

SoS o

C

CL

E

-Complement control protein (CCP)

-Somatomedin B

-C-type Lectin

-Epidermal growth factor (EGF)

-Partial Epidermal growth factor (EGF)

-Potential N-linked glycosylation

-Potential O-linked glycosylation

KEY TO DOMAINS

E

E

E

E

E

E

E

SR-D SR-E SR-F

The Scavenger Receptor Superfamily

LTALPS

Gram-positive bacteriaGram-negative bacteria

Bacterial DNA

E. coliS.aureus

E. coliS.aureus

E. coliS.aureus

Receptors Important in

The Systemic Response to Infection

History of Endotoxin Research




Core LPS Signaling Machineryc. 1990-1996




An Innate Immunity “Time Line”



Use of adjuvant to stimulate the

immune response

Modified from: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)

Discovery of the NF-B signaling pathway by Toll

in Drosophila by Hoffman and colleagues

Molecular basis ofadjuvant discovered

by Medzhitov and Janeway

“Infectious-non-self” model of immunity

described by Janeway

TRAF6 dTRAF

Vertebrates Drosophila

TLR-4 Toll

ECSIT dECSIT

DDDD

TIR domain MyD88 Tube

IRAK Pelle

NF-B

MEKK1

IKK-

p65

Cactus

Dif/Relish

Ird6

extracellular space

cytosol

TAK

IKK- IKK-

MD2

CD14

Adaptor proteins

Kinases

IKK complex

p50

I-B

Receptor Complex

TLR Signaling Components

TIR = Toll/IL-1 receptorDD = Death domainIKK = I-B kinase

NOD Proteins:Intracellular Peptidoglycan Sensors

NF-Bp65p50

I-B

RICK

NodProtein

CARD

LigandRecognition

NOD-1 NOD-2

Recruitment of TLR2 to Yeast Phagosomes

TLR2 Phase Contrast TLR2 TLR2 Phase Contrast TLR2

From: Underhill et al., From: Underhill et al., NatureNature 401:811, 1999 401:811, 1999

From: Luster, Curr. Opin. Immunol. 14:129, 2002

The Dendritic Cell and Development ofThe Primary Immune Response

From: Mellman & Steinman, Cell 106:255, 2001

Dendritic Cell Maturation


The Innate Immune Response OrchestratesDC Trafficking to Secondary Lymphoid Organs

Functional Differences Between

Immature and Mature DCs

Expression of CCR7Migration towards

T-cell zone oflymph node

The (Primary) Acquired Immune Response is Initiated by Innate Immune Recognition


Chemokines Direct Trafficking of Immune Cells

The Dual Role of Defensins inBacterial Immunity

-pleated sheets are represented by green arrows;arginine and lysine residues are shown in blue

From: Perez-Canadillas et al., J. Bio.l Chem. 2001 276:28372

Chemokine CCL20 -defensin BD2

Inflamed defenders. A model of defensin activity in an infected epithelium. Epithelial cells synthesizeantimicrobial defensins (red) both constitutively and in response to infectious and inflammatory stimuli. Other defensins are introduced by the influx of phagocytic cells that use them to kill ingested microbes. Released defensins attract dendritic cells and memory T cells, setting the stage for the adaptive phaseof the immune response. From Ganz, Science 286:420, 1999.

The Role of Defensins in Orchestrating the Immune Response

The Innate Immune Responseto Viruses

The Early Antiviral Response: Cytokines of the Innate Immune System

From: Siegal et al., Science 284:1746, 1999

A Subset of Peripheral Blood Dendritic Cells Produce IFN-

Tracing and isolation of IPCs/pDC2s from human peripheral blood. CD3+ T cells, CD19+ B cells, CD16+ and CD56+ NK cells, and CD14+ monocytes were depleted from blood mononuclear cells by immunomagnetic beads (Dynabeads M-450; Dynal, Oslo, Norway). The cells were stained with anti-CD4-Tricolor (Immunotech, Marseille, France), anti-CD11c-PE (Becton Dickinson, San Jose, California), and a mixture of fluorescein isothiocyanate-labeled antibodies to CD3, CD15, CD16, CD20, CD57 (Becton Dickinson), CD14 (Coulter, Miami, Florida), and CD34 (Immunotech). Within the lineage-negative population (A), CD4+CD11c IPCs and CD11c+ immature DCs were isolated (B). IPCs are plasmacytoid by Giemsa staining (C) and contain rough endoplasmic reticulum and Golgi apparatus under transmission electron microscopy (D). The CD11c+ blood immature DCs display dendrites (E and F)

The Antiviral Response: a

Cascade of Transcriptional Events

Multiphasic induction of murine type I IFN genes can be divided into three phases. (a) The immediate early phase. Virus infection stimulates a phosphorylation cascade, leading to the activation of at least three families of transcription factors, including NF-B, AP-1 and IRF3. Activation of the IFN- promoter requires all three transcription factors. (b) IRF7 induction phase. Secretion of early IFN produces an autocrine response through stimulation of the JAK-STAT pathway. Among the pathway’s target genes is IRF7, itself. (c) Delayed early (amplification) phase. Many members of the IFN- gene family possess promoter binding sites for activated IRF7 and become transcriptionally active.

Some targets of IRFs

Gene Functionp21 Cell cycle arrestIL-15 NK cell maturationFasL Cell deathIL-12 Th1 immune response

CD56bright natural killer (NK) cells are the major producers of NK-derived cytokines following activation of monocytes. (a) During the innate immune response, when macrophages (M) encounter pathogens they produce a variety of cytokines which can then activate the production of IFN- by NK cells. In turn, NK-cell-derived IFN- is requisite for the elimination of intracellular pathogens and the further activation of production of cyotkines by M. In this setting, the CD56bright NK-cell subset produces significantly more IFN- protein compared with the CD56dim NK-cell subset, as shown in (b). Resting CD56bright and CD56dim NK cells were co-cultured with autologous, lipopolysaccharide (LPS)-activated macrophages (M + LPS) in vitro. Note that NK cells cultured with unstimulated M did not produce IFN-. Data represent the mean ± SD of 7 experiments.

(From: Cooper et al., Trends Immunol. 22:633, 2001)

NK Cells are an Important Early Source of IFN-

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The Innate Immune Response to Bacterial and Fungal Infections