Host response signatures to invasive aspergillus

Teresa Zelante

University of PerugiaMicrobiology Section

EUKARYOTIC CELL, Nov. 2007, p. 000 Vol. 6, No. 111535EUKARYOTIC CELL, Nov. 2007, p. 000 Vol. 6, No. 111535--9778/07/$08.000 doi:10.1128/EC.9778/07/$08.000 doi:10.1128/EC.

……HoweverHowever, , virulencevirulence isissecondarysecondary toto the immune the immune

status of the status of the hosthost

The The The cellcellcell wallwallwall

The The The resistanceresistanceresistance tototo

OxidativeOxidativeOxidativeStressStressStress

The The The surfacesurfacesurface

The fungal The fungal The fungal growthgrowthgrowth

A A saprophiticsaprophitic lifestylelifestyle

Innate and adaptive immunity to fungi

Disease occurs in patients with:Disease occurs in patients with:

Suppressed cellular Suppressed cellular defencesdefences (corticosteroids(corticosteroids……))

Absent cellular Absent cellular defencesdefences ((neutropenianeutropenia))

NonNon--neutropenicneutropenic patientspatients

In concomitance with graft versusIn concomitance with graft versus--host diseasehost disease

Patients with Patients with IRS (immune reconstitution syndrome)IRS (immune reconstitution syndrome)

InflammationInflammation

“Control of both might confer an evolutionary advantage whereby the host effectively fights infection but limits collateral immunopathology.” TRENDS in Microbiology Vol.14 No.4 April 2006

InfectionInfection

ImmunopathologyImmunopathology

“inflammation and cancer”Alberto Mantovani Nature 448, 547-548(2 August 2007)

“inflammation: friend or foe?”

“the first line of defense”

AlveolarAlveolar MacrophagesMacrophages

PTXPTX33

PTX3PTX3

Non-redundant role of the long pentraxin PTX3 in anti-fungal

innate immune response

C. neoformans

C. albicans

A. fumigatus

Nature 420, 2002Nature 420, 2002

OO22..--

TLR2TLR2

TLR4TLR4OO22

..--

ILIL--1010

“the first line of defense”

AlveolarAlveolar MacrophagesMacrophages

InflammationInflammation

PTXPTX33

PTX3PTX3

NeutrophilsNeutrophilsTLR6TLR6

TLR9TLR9

DegranulationDegranulation

Chronic Chronic candidalcandidal diseasesdiseases

Severe forms of endemic mycosesSevere forms of endemic mycoses

NonNon--neutropenicneutropenic patients with patients with aspergillosisaspergillosis

Among the omeostatic mechanisms

High levels of IL-10 are detected in:

A A causecause or a or a consequenceconsequence??

High levels of IL-10 are detected

VOLUME 7 | JUNE 2007NATURE REVIEWS | IMMUNOLOGY

IMMUNOLOGICIMMUNOLOGICTOLERANCETOLERANCE

Bone MarrowTransplants

Solid OrganTransplants Autoimmune

Diseases

Infectious Diseases/Vaccine Development

AllergicDiseases

Protective tolerance to fungi:Protective tolerance to fungi:

not a failure to recognize antigens

an active specific response

Th1 + Treg cells

Trends Immunol. 2006, 14:183-9

Tolerance and fungi…

kDa50

MC

22

MC

24

A. F

umig

atus

infe

cted

DCs

_ Infe

cted

PMNsIF

N-γ

-trea

ted

PMNs

_

_ Infe

cted

_

42

kDa42

Lung

0

4

8

Lung

Kynu

reni

ne(m

M)

*

_

Infection

Treatment _ Cyclop._

++

Cyc

lop.

IDO expression in Aspergillosis

Indo

Indo

Blockade of IDO EXACERBATES INFECTION

0

10

20>60

0

25

50

MST

CFU

x10

3

*

*

Lung

Infection

1-MT_ + _ +

Treatment

++ + +

Cyclop. Cyclop.__

Infection

1-MT_ + _ +

Treatment

++ + +

Cyclop. Cyclop.__

AllergyAllergy

pDCpDC

IDOIDO

InflammationInflammation

Dendritic cellsDendritic cellsThe Host Responses: the adaptive line of defense

nTregnTregILIL--1010

iTregiTregILIL--1010

TGFTGF--ββ

IFNIFN--γγ

IDOIDO

NeutrophilsNeutrophilsTh2Th2

Infection and Allergy toInfection and Allergy toAspergillus:Aspergillus:

The hygiene hypothesisThe hygiene hypothesisin actionin action

Treg cells in motion

CD25+

Tregs

CD4+CD25-

Tcells

PMNsINNATE

IMMUNITY

ADAPTIVE IMMUNITY

IDOIDO++DC and Treg cells in AspergillosisDC and Treg cells in Aspergillosis

J. Immunol. 2005, 174:2910

Late

B7-2B7-1IDO

Inhibition of allergy

iTreg

IL-10 TGF-β

Th2

EarlyC

TLA-

4B

7-1

IL-10

nTreg

Inhibition of inflammation

PMNIDO

IDO+

pDC

Germinating conidia

IFN-γ

CTLA-4

B7-1

The Toll pathway to protective tolerance to Aspergillus

e l

Tlr2–/–

e l

Tlr3–/–

e l

Tlr4–/–

e l

Tlr6–/–

e l

Tlr9–/–

e l

MyD88–/–

e l

Trif–/–

e l

C57BL/6+

-

CFU

mild mild severe severe severe mild mild severeInfection

mild severe ? mild mild severe mild ?Allergy

Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy

Grohmann U et al. Nat Med. 2007;13:579Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its

natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis.

Reverse signaling through GITRL initiates the immunoregulatory pathway of tryptophancatabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-kappaB-dependent induction of indoleamine 2,3-dioxygenase (IDO).

Dexamethasone activated IDO through the symmetric induction of GITR in CD4(+) T cells and GITRL in plasmacytoid dendritic cells and exerted IDO-dependent protection in a model of allergic airway inflammation.

Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.

The Th17 pathway: An emerging subset

The Th17 pathway: An emerging subset

ItIt’’s s fillingfilling a gap in a gap in understandingunderstanding inflammationinflammation

NeutralizationNeutralization resolvesresolves tissuetissue pathologypathology in in AutoimmunityAutoimmunity

IL17 A IL17 A hashas a a nonnon--redundantredundant rolerole in in neutrophilneutrophil recruitmentrecruitment

ILIL--23 23 regulatesregulates PMN PMN homeostasishomeostasis

GoodGood or bad?or bad?

p19 and p35: two closest “neighbourns”

NNatureature reviews immunology volume 5 | reviews immunology volume 5 | julyjuly 2005 | 5212005 | 521

C57BL6C57BL6 p19p19--//-- p35p35--//-- p40p40--//--

Th17 pathway correlates with susceptibility to Th17 pathway correlates with susceptibility to aspergillosisaspergillosis

Chi

tinC

hitin

(( μμg g

gluc

osam

ine

gluc

osam

ine //

orga

nor

gan ))

0

5

10

WT p35-/- p40-/-p19 -/-

The Th1/Th17 pathways are crossThe Th1/Th17 pathways are cross--regulated in regulated in aspergillosisaspergillosis

p35p35

p19p19

ILIL--1212ββ2R2R

ILIL--23R23R

0

5

10

0

5

10

0

5

10

0

5

10

+ + + +−− −−

mR

NA

fold

incr

ease

*

**

**

*

**

**

*

*

WT p35-/- p40-/-p19 -/-

0

5

10

Chi

tinC

hitin

(( μμg g

gluc

osam

ine

gluc

osam

ine ))

IFN

IFN

-- γγ++

CD

4C

D4++

ILIL-- 1

2p70

12p7

0

* *

*

** **

0

150

300

0

25

50

*** **

none αIL-23 αIL-17Ct

none αIL-23 αIL-17Ct

ILIL--23 and the Th17 pathway are 23 and the Th17 pathway are causallycausally linked linked to susceptibility to to susceptibility to aspergillosisaspergillosis

none αIL-23 αIL-17Ct

%

% k

illin

gki

lling

p19p19--//-- p35p35--//--C57BL6C57BL6

*

*

ILIL--23 and IL23 and IL--17 impair 17 impair effectoreffector function andfunction and……

0

50

100

0

5

10

0

150

300

− − −− −− − +

+−−

+

− − −− −− − +

+−−

+

IFNIFN--γγILIL--2323ILIL--1717

MM

PM

MP --

9 9 ar

bitr

ary

arbi

trar

yun

itsun

itsM

P0

MP0

arb

itrar

yar

bitr

ary

units

units

*

IFNIFN--γγILIL--2323ILIL--1717

− − −− −− − +

+IFN-γIL-23IL-17

−−

+−++ +

−+

* ***

*

0

50

100

kDa 42

β-tubulin

MC

22

MC

24

− − −

− −

− − +

+IFN-γ

IL-23

IL-17

−

−+

−+

+ +−

+

……subvert the antisubvert the anti--inflammatory program of PMNinflammatory program of PMN

IDO IDO negativelynegativelyregulatesregulates the the inflammatoryinflammatory

program of PMNprogram of PMN

How How TLRsTLRs are strictly involved?are strictly involved?

Nature rev.Imm.january 2008 | volume 8

0 100 2000 100 2000 100 200 0 100 200

NoneYeastsConidia

Stimulus

C57BL6 TLR-2-/- TLR-4-/- MyD88-/- TRIF-/-

**

**

**

**

**

0 100 200

ILIL--23 production by 23 production by DC DC isis promotedpromoted

ILIL--12 p35 12 p35 deficiencydeficiency

TRIF TRIF deficiencydeficiency

TIR8/SIGIRR TIR8/SIGIRR deficiencydeficiency

NADPH NADPH oxidaseoxidase deficiencydeficiency

Th17 pathway Th17 pathway expressionexpression

DefectiveDefective fungal fungal clearanceclearance

TIR8/SIGIRR TIR8/SIGIRR deficiencydeficiency

NADPH NADPH oxidaseoxidase deficiencydeficiency

ChronicChronic granulomatousgranulomatous diseasedisease

DefectDefect in p47in p47phox phox subunitsubunit of the NADPH of the NADPH

oxidaseoxidase

HyperinflammatoryHyperinflammatory phenotypephenotype

RecurrentRecurrent fungal and fungal and bacterialbacterial infectionsinfections

IFNIFN--γγ therapytherapy

Th1 Th17

IFN-γ IL-17

IDO+ IDO-

CONCLUSIONS

TregTh1 Th2 Th17

Fungal clearance

AllergyImmuno

suppression

Promotion of inflammation and fungal

growth

Autoimmunity

Inhibition of innate and adaptive

inflammation

Memory

““Nature strives after opposites towards perfectionNature strives after opposites towards perfection””

AristotleAristotle

Microbiology Section

Silvia Bozza Antonella De LucaCarmen D’AngeloPierluigi BonifaziSilvia MorettiGloria Giovannini

Luigina Romani

Pharmacology Section

Carmine VaccaMaria L. BelladonnaFrancesca Fallarino

Paolo Puccetti

Acknowledgements

THANK YOU

Division of Exp. Medicine, Buffalo

Brahm Segal