brown fungal infections killers

7/21/2019 Brown Fungal Infections Killers

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Hidden Killers: Human Fungal InfectionsGordon D. Brown et al.Sci Transl Med 4, 165rv13 (2012);DOI: 10 .1126/scitranslmed.3004404

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D o w n l o a d e d f r o m

s t m . s c i e n c e m a g . o r g

o n D e c e m b e r 2 0 , 2 0 1 2

Science Translational Medicine (print ISSN1946-6234; online ISSN 1946-6242) ispublished weekly, except t he last week inDecember, by the American Association for theAdvancement of Science, 1200 New YorkAvenue N W, Washington, DC 20005. Copyright2012 by the American Association for t heAdvancement of Science; all rights r eserved.The title Science T ranslational Medicine is a

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R E V I E W

M E D I C A L M Y C O L O G Y

Hidden Killers: Human Fungal Infec i!nsG!rd!n D" #r!$n% &' Da(id W" Denning% ) ' *eil A" R" G!$% &' + uar M" Le(i ,%- 'Mi.ai G" *e ea% / ' 0.e!d!re C" W.i e 1'

Al .!ug. fungal infec i!ns c!n ri2u e su2s an iall3 ! .uman m!r2idi 3 and m!r ali 3% .e im4ac !f .ese dis5eases !n .uman .eal . is n! $idel3 a44recia ed" M!re!(er% des4i e .e urgen need f!r efficien diagn!s ic

es s and safe and effec i(e ne$ drugs and (accines% researc. in ! .e 4a .!4.3si!l!g3 !f .uman fungalinfec i!ns lags 2e.ind .a !f diseases caused 23 ! .er 4a .!gens" In .is Re(ie$% $e .ig.lig. .eim4!r ance !f fungi as .uman 4a .!gens and discuss .e c.allenges $e face in c!m2a ing .e de(as a ingin(asi(e infec i!ns caused 23 .ese micr!!rganisms% in 4ar icular in immun!c!m4r!mised indi(iduals"

I*0ROD6C0IO*It is widely accepted that fungal pathogens have anenormous in-fluence on plant and animal life.Indeed, a recent report detailed the extraordinary andfrightening impact of these pathogens on speciesextinctions, food security, and ecosystemdisturbances (1). In contrast, the effect fungalinfections have on human health is not widely recog-nized ( able 1), and deaths resulting from theseinfections are often overloo!ed. "or example, the#orld $ealth %rganization has no program on fungalinfection, and most public health agencies 7 with thesingular exception of the &.'. enters for isease

ontrol and *re-vention ( ) 7 conduct little or nomycological surveillance. +ost people in their lifetimes will suffer from superficial fungalinfections that are generally easy to cure, butmillions of individuals worldwide will contract life-threatening invasive infections that are much harder to diagnose and treat ("ig. 1).

%f particular concern is the high rate of mortalityassociated with invasive fungal infections, which oftenexceeds despite the availa-bility of severalantifungal drugs ( able 1). he purpose of this /eviewis to estimate, from available scattered data, the disease

burden caused by these pathogens0 describe the typesand impact of fungal infections worldwide0 andillustrate the pressing need for more research in thisfield to facilitate the development of better diagnostictests and therapies and of as yet unrealized preventativevaccines. Indeed, funding for med-ical mycology isgreatly underrepresented when compared to other in-fectious diseases, although this may also reflect thenumber of applications for funding in the area. "or

example, from the total spent over the last years onimmunology and infectious disease research by the#ellcome rust (a &. . charitable body), the &. .+edical /e-search ouncil, and the &.'. 2ationalInstitutes of $ealth (2I$), only 1.3 to 4. wasallocated specifically to medical mycology.

F6*GI A*D H6MA* DI+EA+E

'uperficial infections of the s!in and nails are the mostcommon fun-gal diseases in humans and affect 54(or 51.6 billion) of the general

& A2erdeen Fungal Gr!u4% Ins i u e !f Medical +ciences% 6ni(ersi 3 !f

A2erdeen% A2erdeen A#)1 )8D% 6K") *a i!nal As4ergill!sis Cen re Educa i!nand Researc. Cen re% 6ni(ersi 3 H!s4i al!f +!u . Manc.es er% Manc.es er M)-9L0% 6K" - De4ar men !f Medicine%6ni(ersi 3 !f Massac.use s Medical+c.!!l% W!rces er% MA &; 1% 6+A"/ De4ar men !f In ernal Medicine and .e*i


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h are the second most numerous agents of fungalinfection worldwide.

Invasive fungal infections have an incidence thatis much lower than superficial infections, yetinvasive diseases are of greater concern because theyare associated with unacceptably high mortalityrates. +any species of fungi are responsible for theseinvasive infections, which !ill about one and a half million people every year. In fact, at least as many, if not more, people die from the top 1 invasive fungal

diseases ( able 1) than from tuberculosis ( ryptococcus, andida, ;spergillus,and*neumocystis. $owever, epidemiological data for fungal infections are notoriously poor because fungalinfections are often misdiag-nosed andcoccidioidomycosis (also sometimes called valleyfever ) is the only fungal disease that must bereported to the . he sta-tistics presented in

able 1 have been largely extrapolated from the few(mostly geographically localized) studies that have

been performed (also see 'upplementary +aterials)and are undermined by the lac! of accurate incidencedata from many parts of the developing world. on-se?uently, our calculations may significantlyunderestimate the true burden of invasive fungaldiseases.

he immune system of healthy individuals haseffective mecha-nisms for preventing fungalinfections, and the current incidence of invasivediseases is largely a result of substantial escalationsover the last few decades in immunosuppressiveinfections, such as $I9:;I ',


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R E V I E W

and mod

er n immunosu

p p

r e

ssiveandinvasivemedical

interventions."or example,thevastma

@ori

tyof

patientswithcr yptococ

cosis7for whichwehavecom

parative

lystr

on

Fig" &" Remar>a2le fungal infec i!ns" ?0!4% lef ! rig. @ C.r!nic muc!cu ane!us candidiasis% c.r!5m!2las !m3c!sis% and mucicarmine5s ained .is !l!gical sec i!n !f .e cere2ellum !f an AID+ 4a ien$.! died fr!m cr34 !c!ccal mening!ence4.ali is ?dem!ns ra ing an a2undance !f 4in>5s ained fungi@"?#! !m@ C!m4u ed !m!gra4.3 ?C0@ scan !f .e lungs !f a 4a ien s.!$ing a large fungal 2all?as4ergill!ma% 2lac> 2! @% $.ic. $as surgicall3 rem!(ed ?rig. @" 0.ree smaller ca(i ies are als! (isi2lein .e C0 scan ?red arr!$s@% $.ic. is 34ical !f c.r!nic 4ulm!nar3 as4ergill!sis"


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1 million

cases,with mor

e than ines

.a

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.e

!ler ance mec.anisms

necessar 3

! 2al


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ance inf lamma

i!n and

issu

e damage" H!$e(er % $.en ac

i(a

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el3!r

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r !ngl3%

.ean

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amma

!r 30

H

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cellr es4!nsescan

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mage"H!$e(er %$.en ac

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mma

!r 3 0

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) and

!

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!r 3

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24/74

can d!$n5r egula

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52ili

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i!n"CREDI0:C"#ICKEL

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$ $$


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R E V I E W

human h

ost("ig.4).%ne

pr ominent

br ea

! thr ough wasan

a

p pr eciation

of theimportanceof innate-immune

oll-li!ereceptors( A/s)inan-timicro

bialhostdef ense.

A/swer eoriginallyide

ntif iedinfruitflies asessentialcomponents

for thedevelo

pmentof resistancetoinfection

with;spergillus(andlater ,other fungi).

hediscover y of

A/sas!ey

playersinhum

aninnateimmunity

broughttheseso-called

patt

ernrecognitionrece

p-

tor s (*/

/ s) to the att

Fig" -" Diagn!s ic dilemma" A re4resen a i(e clinical scenari! .a dem!ns ra es .e magni ude !f 4r!2lemsass!cia ed $i . .e diagn!sis !f fungal infec i!ns $i . curren diagn!s ic !!ls" 0.e figure s.!$s .e diagn!s icc!nsidera i!ns% s ar ing $i . .e !rgan .a ma3 2e in(!l(ed ?inner circle@% .e m!s li>el3 diagn!ses ?middlecircle@% and .e es ing reJuired ! rule in !r !u eac. !f .ese diagn!ses ?!u er circle@" Cer ain fea ures !f .eillness ma>e s!me diagn!ses muc. m!re !r less li>el3% in 4ar icular% .e 4a ien Bs ra(el .is !r3 and s>in4a4ule% $.ereas ! .er a2n!rmali ies are n!ns4ecific" 0.e 4a ien is a 1-53ear5!ld man ?4.! !gra4. dis4la3edunal ered% $i . 4ermissi!n fr!m 4a ien @ admi ed af er .a(ing 2een increasingl3 un$ell f!r & da3s des4i eadminis ra i!n !f !ral an i2i! ics" He .as a 4re(i!us .is !r3 !f 4neum!nia ?) 3ears earlier@% is a - 4ac> 4er 3ear sm!>er% and a>es &1 mg !f 4rednis!l!ne ?a c!r5 ic!s er!id@ and 1 mg !f a,a .i!4rine ?animmun!su44ressi(e agen @ f!r in ers i ial lung disease" He .as ra(eled e ensi(el3 in .e 6ni ed + a es%s!u .ern Eur!4e% and .e Middle Eas " On admissi!n% .e .ad a fe(er !f - "- C% $as slig. l3 c!nfused 2u full3c!nsci!us% .ad ! 3gen sa ura i!ns !f 9/ % .ad a 2l!!d 4ressure !f 91 ; ?l!$@% .ad a ne$ n!nulcera ed dar>4a4ule !n .is rig. l!$er arm & cm acr!ss% and .ad n!ns4ecific general $.ee,ing in .is c.es " He .ad aslig. l3 raised $.i e 2l!!d cell c!un $i . neu r!54.ilia% a raised serum crea inine indica i(e !f significan l3im4aired renal func i!n% and nega i(e 2l!!d cul ures" *ine m!n .s earlier% an HIV an i2!d3 es .ad 2een4erf!rmed f!r em4l!3men 4ur4!ses and $as nega i(e" His c.es radi!gra4. s.!$ed slig. l3 increased.a,iness 2ila erall3 and s.!$ed n! im4r!(e5men af er -; .!urs !f rea men $i . 2r!ad5s4ec rum an i2i! ics"

HO0O CREDI0: G" WHI0EH6R+0


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ention of

the entir e scientif ic community and

2o

bel

pr izes in +ed

icine to s

cientists Eules $of f man and Dr uce Deutler

in 4

11. "ung

al r ecogni

tion

by the innate immune system also led

to the discov


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er y of ano

ther class of mammalian */ / s, the

-ty

pe

lectin r ece

pto

r s (

A/ ),

as well as the identif ication of new intr

a-cellular sig

naling

pat

hways modulated

by

A/ s (3=). It tur ns ou

t that ther e a


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r e hun-dr e

ds of

A/ s

but only 11

A/ s encoded

by th

e human genome

. 'o it is

not sur -

pr ising that

A/ s ar e now r ecogn

ized to

play a

pr edomina

nt r ole in antif ungal im-munity (

). In

humans, def ici


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encies and

polymor

phisms in

both */ / systems wer e s

u bse?uently f o

und to cau

se susce

pti

bility to a r ange of f ungal in

f ections (

1).

%ur under standing of ada

p

tive im-munity has also

benef ited f r om the


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r esear ch on antif ungal ho

st def ense. ;lthough scientists had f unctio

nally divided the di-ver s

e

po

pulation of immune-r egulator y

3F

he

l per (

$

)

cells in humans into

$

1 cells (cr itical f o

r

pr otective an


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tif ungal immunity) and

$

4 cells (gener

ally non-

pr otective dur ing f u

ngal inf ections),

$

16 cells wer e ident

if ied only r ecently in the co

ntext of autoimmune disea

ses.

$

16 cell

s ar e now r ecognized to

play


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essen-tial r oles in

pr ote

ctive antif ungal im-munity at mucosal sur f a

ces such as in the lungs

and mouth. Indeed, genetic def ects in

$

16

r es

ponses r ender

patients

susce

pti

ble to chr onic mucosal f ungal inf e


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ctions, such as occur s in

hy

per immu-noglo

bulin B syndr ome, which r es

ults f r om mutations in th

e gene ('

;

7) that encodes the signal tr an

sducer and activa-tor of

tr anscr i

ption 7 ('

;

7)

pr otein (

4), or in


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autosomal dominant chr on

ic mucocutaneous candidiasis, caused

by mu-

tations in the '

;

1 gene

(

7,

3) ("ig. 1). $owever , unli! e f or oth

er

pathogens, the

br oader

identif ication of f actor s that con-tr i

bute


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to f ungal susce

pti

bility

7f or exam-

ple, thr ough genome-wide associat

ion studies7has

been ham

p

er ed

by the lac! of lar ge

patient cohor ts.

;lthough w

e have made signif icant adv

ances in our under standing

o


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f the unde

r lying mechanisms of

pr otec

tive

immunity,

par ticular ly to invasive inf ections with ;s

per gillus,

andi-da,

and

r y

ptococc

us, ther e r emains much to

be lear ned. "or


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exam

ple, t

her e ar e still

no antif ungal vaccines, and we ! now littl

e a

bout th

e immuno

pathol

ogical

pr ocesses of the common noninvasive

f ungal in

-f ections, suc

h as r ecur r ent vulvovaginal candidiasis or


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der mato

ph

yto-sis. +or eo

ver , little is ! nown a

bout immunity to mos

t other f u

ngal


40/74

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R E V I E W

pathoge

ns,es

pecially

emer ging

pathogens (such as the less-commo

nfilamentousfungi)and

endemicdiseasesindevelopingcount

riessuchas

par acoccidioidomycosis.

h

e potentialroleof fungal

pathogensin

theimmune

pathologyof inflammator y

andautoimmunedis

eases7for exam

ple,

r ohnBsdis

ease,sar coidosis,colitis(

),and

arthritis7alsore-?uiresattention

byscientists.

CLI*IC

AL

A

R+%n


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exam

ple,a

blood cultur e hasa sensitiv

ity of 5

f or invasive cand

idiasisand

for invasiveaspergi

llosis.;lthoughtheidentif icationof someinfec-tions isrelativelystraightfor war d7such as

thedetectionof cry

ptococcalantigens inthe

bloodandcer ebr ospinalfluidusinganew

pointof car edipstic! test( s!u!f

.e!44

!runis ic2!"*a"Re("Micr!2i!l"9%&9-

) -?)

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1

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. N"R"Har ris%+"R"L!c>.ar%E"De2ess%*"Mar sde

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l2l!!ds

r eam inf ec

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Anal3s

is !f )/%&

9 cases f r !m a 4r !s4ec

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1

6.+an

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!f fungaemiaandnum2ers!f is!la es$i.reduceda,!lesusce4 i2ili3"Clin"Mic

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4.W"Warn!c>%Incidence!f 2l!!ds r eam

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