host response signatures to invasive aspergillus · host response signatures to invasive...
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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?”
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??
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
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
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
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
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
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