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ono
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er
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i
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A
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In
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roduc
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Th
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t
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l
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e
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t
s
immuno
comp
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s
ed
ind
i
v
idu
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l
s[
1
]
.IPAh
a
sb
e
enad
i
s
e
a
s
eo
fg
row
in
gcon
c
e
rno
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en
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ad
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e
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o
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omp
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t
ion
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e
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e
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r
ap
yt
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e
a
tm
en
t
s
inc
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e
rp
a
t
i
en
t
s[
2
]
.Inadd
i
t
ion
,th
e
r
e
i
s
in
c
r
e
a
s
in
ge
v
id
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eth
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anspo
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ad
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c
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l
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e
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op
inc
e
r
t
a
in
immun
o
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omp
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t
en
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l
a
t
ion
s[
3
]
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r
r
en
t
l
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e
r
ea
r
enoa
v
a
i
l
ab
l
ev
a
c
c
in
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rA
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fum
i
g
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tu
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andan
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i
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ld
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a
v
ea mod
e
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e
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s
in
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im
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t
in
gh
i
gh mo
r
t
a
l
i
t
yr
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t
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c
a
l
l
y
du
et
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a
t
ed
i
a
gno
s
i
so
fIPA[1
,
2
,
4
]
. Mo
r
eo
v
e
r
,th
er
e
c
en
tem
e
r
g
en
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a
lc
a
s
e
sandg
eo
g
r
aph
i
ca
r
e
a
s[
5
,
6
,
7
]
.
3
Th
econ
c
en
t
r
a
t
iono
fA
s
p
e
r
g
i
l
lu
scon
id
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ina
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amp
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rom0
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/m
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san
ind
i
v
idu
a
lc
an
inh
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l
ehund
r
ed
so
fcon
id
i
a[
8
]
.In mo
s
t
immuno
com
p
e
t
en
t
ind
i
v
idu
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l
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econ
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s
em
in
a
t
es
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t
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i
c
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l
l
y[
9
,
1
0
]
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rund
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r
s
t
and
in
go
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th
e
in
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l
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a
to
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o
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t
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.
.
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i
g
a
tu
sg
row
th
inth
e
lun
gdu
r
in
g
in
v
a
s
i
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sh
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gh
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on
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r
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r
ap
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t
i
v
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t
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f
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a
t
e
immun
ec
e
l
l
s
,
in
c
lud
in
gn
eu
t
roph
i
l
s[
1
1
]
,
in
f
l
amm
a
t
o
r
ym
on
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c
y
t
e
s[
1
0
,
1
2
]
,NKTc
e
l
l
s[
1
3
]
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l
a
sm
a
c
y
to
idd
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i
t
i
cc
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l
l
s[
1
4
]
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e
imp
o
r
t
an
c
e
.
fum
i
g
a
tu
si
sh
i
gh
l
i
gh
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ko
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ro
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and m
i
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e
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g
h
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l
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gIPAa
f
t
e
rA
.
fum
i
g
a
tu
sch
a
l
l
en
g
e[
1
5
,
1
6
,
1
7
]
.Fu
r
th
e
rm
o
r
e
,p
a
t
i
en
t
swh
ob
e
com
en
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t
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t
e
rch
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e
r
ap
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rabon
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a
r
rowt
r
an
sp
l
an
ta
r
ea
ta
PLOSPa
thogens
|DO
I
:10
.1371
/
jou
rna
l
.ppa
t
.1004625 Janua
r
y28
,2015
2
/25
Ro
leo
f
IL
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y
to
k
ine
sa
f
te
rA
spe
rg
i
l
lu
sfum
iga
tu
sCha
l
lenge
h
i
gh
e
rr
i
s
kf
o
rd
e
v
e
lop
in
gIPA[1
8
,
1
9
,
2
0
,
2
1
]
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e mu
r
in
e mod
e
lo
fA
.
fum
i
g
a
tu
sin
f
e
c
t
i
on
,
CXCR
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i
t
s
l
i
g
and
sa
r
e
impo
r
t
an
ts
i
gn
a
l
in
gcompon
en
t
sfo
rn
eu
t
roph
i
lr
e
c
ru
i
tm
en
t
[
2
2
,
2
3
,
2
4
]
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eab
s
en
c
eo
fCXCR
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i
gn
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l
in
gdu
r
in
gpu
lmon
a
r
yA
.
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i
g
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tu
sin
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e
c
t
i
on
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e
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i
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r
e
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s
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roph
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r
e
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ed m
o
r
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a
l
i
t
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a
t
e
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im
i
l
a
rtoan
eu
t
rop
en
i
c mod
e
l[
2
3
]
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i
t
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a
l
l
y
,aro
l
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rCCR
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i
gn
a
l
in
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e
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a
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l
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i
g
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tu
sin
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e
c
t
i
on
[
1
0
,
1
2
]
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ow
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v
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r
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ts
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e
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Inadd
i
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th
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e
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l
ymo
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i
sm
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inth
eIn
t
e
r
l
eu
k
in(
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s
t
e
r
m
a
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e
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t
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t
ind
e
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ep
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l
i
t
yo
rr
e
s
i
s
t
an
c
etoIPA
inhum
an
s[2
5
,
2
6
]
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1
β
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sw
e
l
la
s
Th
eIL
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en
ec
lu
s
t
e
rcod
e
sfo
rtwop
ro
in
f
l
amm
a
to
r
yc
y
to
k
in
e
s
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1αandIL
th
eIL
1r
e
c
ep
to
ran
t
a
gon
i
s
t(
IL
1R
a
)[
2
7
]
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l
lth
r
e
eo
fth
e
s
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am
i
l
ym
emb
e
r
sb
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oth
e
IL
1r
e
c
ep
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r
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yp
eI(
IL
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)
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eth
e
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e
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l
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a
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omp
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PLOSPa
thogens
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rna
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PLOSPa
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|DO
I
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rna
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.1004625 Janua
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8
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Jh
in
g
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ta
l
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r
e
s
sand[
6
1
]
)
.
Inou
re
xp
e
r
im
en
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e
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a
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1
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e
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l
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t
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i
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oph
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i
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an
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c
a
l
l
yandc
l
in
i
c
a
l
l
y
imp
o
r
t
an
t
7
]
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i
ch
i
sc
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e
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o
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t
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g
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i
c
ew
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w
i
th
in
f
l
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a
to
r
y mono
c
y
t
ea
r
r
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v
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ltoth
e
lun
g
s[1
2
]
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e
r
s
t
and
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o
x
i
ac
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an
c
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la
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fm
a
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ep
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n
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romTo
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in
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a
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rodu
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e
spon
s
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e
ru
g
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o
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ach
a
l
l
en
g
e[
6
5
]
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e
rh
ap
s
s
om
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tsu
rp
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s
in
g
l
y
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8
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t
i
fun
g
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la
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i
v
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t
ya
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in
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g
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tu
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o
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ar
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a
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c
t(
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in
g
r
anA
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ta
l
,
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e
s
s
)
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th
a
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enshown
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rfun
g
a
lp
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o
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en
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a
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r
e
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r
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la
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o
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c
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od
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e
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r
a
s
i
l
i
en
s
i
s[
6
6
,
6
7
]
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i
t
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a
l
l
y
,I
l
1
r
1
-andN
l
r
p
3-d
e
f
i
c
i
en
tm
a
c
r
o
.b
r
a
s
i
l
i
en
s
i
s[
3
4
]
.Incon
t
r
a
s
t
,du
r
in
gd
i
s
s
em
ph
a
g
e
sh
a
v
e
imp
a
i
r
edan
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i
fun
g
a
la
c
t
i
v
i
t
ya
g
a
in
s
tP
in
a
t
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and
id
i
a
s
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s
I
l
1
a
-d
e
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i
c
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en
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a
sa
s
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c
i
a
t
edw
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thd
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c
r
e
a
s
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t
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fun
g
a
la
c
t
i
v
i
t
yo
f
l
eu
k
o
c
y
t
e
s[
4
1
]
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s
,s
tud
i
e
sd
e
s
i
gn
edtound
e
r
s
t
andth
ed
i
f
f
e
r
en
t
i
a
ld
ep
end
en
c
i
e
so
fth
eIL
1
c
y
t
o
k
in
e
s
inr
e
gu
l
a
t
in
g
l
eu
ko
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y
t
er
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c
ru
i
tm
en
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t
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fun
g
a
la
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t
i
v
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t
ydu
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in
gar
an
g
eo
ffun
g
a
l
d
i
s
e
a
s
e
sand mo
rpho
lo
g
i
c
a
lfo
rm
sa
r
en
e
ed
ed
.
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i
t
i
ontound
e
r
s
t
and
in
gth
ec
e
l
lu
l
a
rsou
r
c
eo
fIL
1
αandIL
1
β
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e
r
s
t
and
in
gth
e
in
f
l
amm
a
t
o
r
yp
a
thw
a
y
s
l
e
ad
in
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xp
r
e
s
s
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fIL
1
αandIL
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βa
r
ee
s
s
en
t
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a
ltoou
rund
e
r
s
t
and
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go
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e
s
i
s
t
an
c
etoIPA
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eab
s
en
c
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fd
e
c
t
in
1s
i
gn
a
l
in
gth
e
r
e
i
sd
e
c
r
e
a
s
ede
xp
r
e
s
s
i
ono
f
b
o
thIL
1αandIL
1
β[
6
8
,
6
9
]
.Th
e
lo
s
so
fH
IF
1
αinth
eL
y
sM
e
xp
r
e
s
s
in
gc
e
l
l
sa
l
s
or
e
su
l
t
ed
in
d
e
c
r
e
a
s
edIL
1αl
e
v
e
i
g
a
tu
s
ch
a
l
l
en
g
e[
6
0
]
,wh
i
chc
anb
er
e
gu
l
a
t
edb
yd
e
c
t
in
1
.fum
l
s
a
f
t
e
rA
a
g
on
i
s
t
ssu
cha
sβ
g
lu
c
an[
7
0
]
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lmon
a
r
yA
.
fum
i
g
a
tu
sin
f
e
c
t
ionr
e
su
l
t
s
ins
i
gn
i
f
i
c
an
tt
i
s
su
e
d
am
a
g
eandc
e
l
ld
e
a
th
,bu
tth
ee
x
a
c
tt
yp
eo
fc
e
l
ld
e
a
th
i
sno
tknown
. Mo
r
eo
v
e
r
,th
eph
en
o
t
yp
e
o
fc
e
l
ld
e
a
thw
i
l
lb
esh
ap
edb
yth
eh
ypo
x
i
cm
i
c
ro
en
v
i
ronm
en
tfounddu
r
in
gIPA
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et
yp
eo
f
c
e
l
lu
l
a
rd
e
a
tho
c
cu
r
r
in
ginv
i
v
o
du
r
in
gA
.
fum
i
g
a
tu
sw
i
l
lh
a
v
e
impo
r
t
an
t
immuno
l
o
g
i
c
a
l
im
p
a
c
t
ssh
ap
in
gth
ee
a
r
l
yIL
1αandIL
1
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e
spon
s
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e
c
au
s
en
e
c
ro
t
i
cc
e
l
ld
e
a
thf
a
v
o
r
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e
l
e
a
s
ewh
i
l
ep
y
rop
to
s
i
sf
a
vo
r
sIL
1
βr
e
l
e
a
s
e[
7
1
]
.In
t
e
r
e
s
t
in
g
l
y
,C
.a
l
b
i
c
an
smu
t
an
t
sw
i
thd
e
f
e
c
t
s
in
indu
c
in
gp
y
rop
to
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i
sa
l
sod
emon
s
t
r
a
t
edd
e
f
e
c
t
s
in
indu
c
in
gIL
1
βs
e
c
r
e
t
ion
,bu
tIL
1
αr
e
l
e
a
s
e
w
a
sn
o
te
x
am
in
ed[7
2
]
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i
t
ion
a
l
l
y
,und
e
r
s
t
and
in
ghowd
e
f
i
c
i
en
c
i
e
s
inPRRs
i
gn
a
l
in
ga
l
t
e
r
s
th
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v
e
r
a
l
l
in
f
l
amm
a
to
r
yr
e
spon
s
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i
l
lb
ec
ru
c
i
a
la
sp
a
t
i
en
t
sw
i
thSNP
s
inPRR
sa
r
ekn
ownt
o
h
a
v
ee
l
e
v
a
t
edr
i
s
k
sfo
rd
e
v
e
lop
in
gIPA[7
3
]
.Ou
rd
a
t
ad
emon
s
t
r
a
t
eth
a
t
inth
eP
y
c
a
r
d-d
e
f
i
c
i
en
t
m
i
c
eth
e
r
ea
r
ee
l
e
v
a
t
ed
l
e
v
e
l
so
fTNFα,CCL
3
,andCCL
4
.On
ee
xp
l
an
a
t
ionfo
ro
b
s
e
r
v
in
ge
l
e
v
a
t
ed
l
e
v
e
l
so
fTNF
α,CCL
3
,andCCL
4cou
ldb
eth
er
an
g
eo
rd
e
g
r
e
eth
a
tPRR
sa
r
eb
e
in
gen
g
a
g
ed
PLOSPa
thogens
|DO
I
:10
.1371
/
jou
rna
l
.ppa
t
.1004625 Janua
r
y28
,2015
16
/25
Ro
leo
f
IL
-1C
y
to
k
ine
sa
f
te
rA
spe
rg
i
l
lu
sfum
iga
tu
sCha
l
lenge
inth
e
P
y
c
a
r
d-d
e
f
i
c
i
en
tm
i
c
eand
/o
rt
empo
r
a
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a
t
i
a
ld
yn
am
i
c
so
ffun
g
a
lc
e
l
lw
a
l
lPAMP
en
g
a
g
em
en
tw
i
thPRR
sinv
i
v
o
th
a
ta
r
eno
tfu
l
l
yund
e
r
s
toodandfu
r
th
e
rcomp
l
i
c
a
t
edb
yaPRR
kn
ownt
ob
een
g
a
g
eddu
r
in
g
in
f
e
c
t
ionnowb
e
in
gab
s
en
t
.
I
t
i
sw
e
l
ld
e
f
in
edth
a
tp
ro
lon
g
edco
r
t
i
co
s
t
e
ro
idt
r
e
a
tm
en
t
in
c
r
e
a
s
e
ssu
s
c
ep
t
ib
i
l
i
t
yo
fh
o
s
t
st
o
IPA[
7
4
]
.In
t
e
r
e
s
t
in
g
l
y
,d
e
x
am
e
th
a
son
e
indu
c
e
sth
ee
xp
r
e
s
s
ionandr
e
l
e
a
s
eo
fIL
1R
I
I[
7
5
]
.
αp
r
o
t
e
in
inth
e
IL
1R
I
I
i
skn
ownto
l
im
i
tth
ea
c
t
i
v
i
t
yo
fIL
1c
y
to
k
in
e
sand
/o
rs
equ
e
s
t
e
rIL
1
c
y
t
o
s
o
l
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r
e
v
en
t
in
gth
ec
l
e
a
v
a
g
eo
fIL
1
αb
yc
a
lp
a
in[6
3
]
.D
e
x
am
e
th
a
son
eh
a
sa
l
s
ob
e
ensh
own
t
o
imp
a
i
rIL
1
αandIL
1
βs
e
c
r
e
t
ionf
romhum
an m
a
s
tc
e
l
l
s
inr
e
spon
s
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s
eud
om
on
a
s
a
e
ru
g
in
o
s
as
t
imu
l
a
t
ion[
7
6
]
. Mo
r
eo
v
e
r
,d
e
x
am
e
th
a
son
et
r
e
a
tm
en
to
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ron
cho
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l
v
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o
l
a
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a
c
r
o
ph
a
g
e
sp
r
i
o
rt
ot
r
e
a
tm
en
tw
i
thA
.
fum
i
g
a
tu
scon
id
i
as
i
gn
i
f
i
c
an
t
l
y
imp
a
i
r
edth
e
i
rr
e
l
e
a
s
eo
f
IL
1
α[
7
7
,
7
8
]
.B
e
c
au
s
ew
eh
a
v
eun
co
v
e
r
edsu
chap
rom
in
en
tro
l
efo
rIL
1
αinc
on
t
r
o
l
l
in
g
.
fum
i
g
a
tu
sch
a
l
l
en
g
e
,fu
tu
r
es
tud
i
e
se
xp
lo
r
in
gth
ec
l
e
a
v
a
g
es
t
a
tu
so
fIL
1
αande
x
pu
lm
on
a
r
yA
p
r
e
s
s
i
ono
fIL
1R
I
I
inc
l
in
i
c
a
l
l
yr
e
l
e
v
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t mod
e
l
sa
r
ec
r
i
t
i
c
a
l
.
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in
a
l
l
y
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e
impo
r
t
an
c
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fapp
rop
r
i
a
t
ea
c
t
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v
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t
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f
l
eu
ko
c
y
t
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s
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ro
lo
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i
g
a
tu
s
i
sh
i
gh
l
i
gh
t
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a
t
i
en
t
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a
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i
gh
l
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s
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ep
t
i
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et
o
A
.
fum
i
g
a
tu
s
[
1
5
,
1
6
,
1
7
]
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t
e
r
e
s
t
in
g
l
y
,CGDp
a
t
i
en
t
so
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c
ea
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et
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c
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l
l
y
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e
r
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l
amm
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t
o
r
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s
t
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t
e
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ch
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l
amm
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som
ea
c
t
i
v
i
t
yandIL
1
βe
xp
r
e
s
s
ion[
7
9
,
8
0
]
.Fu
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Re
fe
rences
1
. B
rownGD
,Denn
ingDW
,GowNA
,Le
v
i
t
zSM
,Ne
tea MG
,e
ta
l
.(2012
)H
iddenk
i
l
le
r
s
:human
funga
l
in
fe
c
t
ion
s
.S
c
iT
ran
s
l Med4
:165
r
v113
.PM
ID
:
23253612
2
. Sega
lBH(2009
)A
spe
rg
i
l
lo
s
i
s
.NEng
lJ Med360
:1870–1884
.
3
. S
te
ven
sDA
, Me
l
i
k
ianGL(2011
)A
spe
rg
i
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