Lecture 15 (10.23) - Host-Pathogen Interactions 1B118

8/10/2019 Lecture 15 (10.23) - Host-Pathogen Interactions 1B118

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Initiation of immuneresponses:

Pathogen recognition:

Janeways Immunobiology (8thed.)

Ch. 3.1-12, Ch. 4


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How cytokines and chemokines recruit neutrophils to site of infectio

1)

Neutrophils go through

blood vessels by rolling onendothelial cells caused by

weak interactions between

adhesion molecules.

2)

Cytokines induce expression

of new stronger-bindingadhesion molecules on

endothelial cells in the site of

infection and on the

neutrophil, plus chemokine

receptors.

3) Chemokinesadhere to

endothelial cells in site of

infection

4)Increased expression of

adhesion molecules slows


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Phagocytosis of a Microbe

Phagocytes destroy pathogens Not less importantly, they (esp. macrophages and

dendritic cells) identify specific pathogen components

and are activated accordingly


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MBL, of the complement system, is

essentially a PRR

The lectin pathway

(MBL mannose binding protein)

PAMP/MAMP

Pathogen/microbe associated molecular

pattern


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Pathogen-associated

molecular patterns (PAMPs/

MAMPs)

Effector Molecules

expression

Antimicrobial peptides / enzymesImmune modulators (co-stimulating

molecules, cytokines etc.)

Signal Transduction

Pathways

The main paradigm of innate immune

recognition relates to membrane PRRs

Pattern RecognitionReceptors (PRR)

PRRs are germline encoded

Recognize broadly-sharedmolecular structures

Initiates signaling by recruiting

proteins and facilitating their

activation

TFs


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The first PRR: The drosophila Toll receptor

initiates innate immune responses

Figure 5. Germinating hyphes of Aspargillus fumigatus(a fungus) on a dead drosophila. Scanning electronmicrograph of a Drosophila adult that succumbed to infection by A. fumigatus and is covered with

germinating hyphae (200

magnification). Cell 1996

TIR domain

Extracellular

Leucine Rich

Repeat domain


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The Leucine Rich Repeat (LRR)~24 aa

LxxLxLxxN

A Toll receptor/TLR has 19-25 tandem repeats

The structural unit of Toll and Toll-

like receptors and many other PRRs


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Vertebrate pattern recognition receptors

common on cells, more so on phagocytes

10-15 TLRs in mammals

(~300 in sea urchin)


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Vertebrate Toll-like

receptors - limited

diversity, yetefficient recognition

of central microbial

components

We know of ~300

different PAMPs

recognized by

TLRs.

(lipoproteins, typicalof Gram +)

(typical of viruses)

(Gram - )


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Signal transduction downstream of Toll and

TLR receptors (option one: MyD88-dependent)

The mammalianToll-like receptor

IRAK

Recruitment of the TIRadaptorprotein MyD88.

Recruits IL1-receptor associated

kinase (IRAK) which gets

activated. Binds the TNF!-receptor

associated factor-6 (TRAF-6) and

activates the TAK1 kinase.

TAK1 phosphorylates the I"B

kinase (I"K) I"K phosphorylates I"Bleading to

its degradation

Released NF-"#enters into the

nucleus and initiates transcription


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TLR activation can take more than one path, initiatingdistinct immune responses

From cellmembrane!

expression of

pro-inflammatory

cytokines

through

MyD88/TIRAP

from endosome

!the anti-viral

type I interferon

response

through TRIF

Type I interferons = IFN-!/$

IL-10=anti-inflammatory cytokine


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Diversity:PRRs include

TLRs, but also

CLRs, RLRs

and NLRs;

recognizingdifferent PAMPs

and localized todifferent cellular

compartments

Similarity:

Downstream,they activate

essentially thesame

transcription

factors

RNA sensors

Sensors of

PAMPs and

of DAMPs


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Innate immune recognition:

TLRs- extracellular or endosomal recognition

NLRs (NOD-like receptors) cytoplasmic

RLRs RIG-I-helicase-like receptors, binding RNAs;

cytoplasmic, recognize nucleic acids.


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Innate immune activation the general scheme


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In macrophages and dendritic cells (DCs)

phagocytosis is accompanied by activation


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Activation of some phagocytic cells

(Macrophages, DCs) is just the beginning

PRR binding to PAMP activates

expression of:

Chemokine receptors (e.g. CCR7,

this one is typical to DCs, help

migrating to lymph nodes)

Co-stimulatory surface proteins

(B7 in the picture)

Secretion of cytokines Enhanced processing and

presentation of pathogen

peptides on type II MHC

Migration to lymph nodes


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Antigen presenting cells are macrophages,

DCs, but also B lymphocytes


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The primary immunological function of Major

Histocompatibility Complex (MHC) molecules is

to bind and "present" antigenic peptides on the

surfaces of cells for recognition (binding) by theantigen-specific T cell receptors of lymphocytes.

MHC class I is expressed by all cells and is

recognized by Cytotoxic T cellsMHC class II is expressed only onAntigen-

Presenting Cells (APCs, Dendritic cells,

macrophages, or B cells) and is recognized by

Helper T cells.

Major Histocompatibility Complexes

(MHCs, aka HLA in humans)


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All nucleated cellsAntigen-presenting cells

Peptidebinding cleft

Major Histocompatability Complex proteins

(MHC; HLA in humans) are surface proteins

used to present pathogen-derived peptides toadaptive immune cells

MHC Class II MHC Class I


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Variability in MHC genes gives rise to unique

combinations of peptides (antigens) presented to the

immune system

Polygenic (~200 genes)

Polymorphic (some genes have ~200 alleles)


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Once activated and loaded, APCs are ready to

activate and recruit cells of the adaptive immunesystem


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the Lymphatic System samples body fluids

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Lecture 15 (10.23) - Host-Pathogen Interactions 1B118