Two unlike cousins: Candida albicans and C. glabrata infection strategies.

0.24 MB·English

by  Brunke, Sascha

CellularMicrobiology(2013)15(5),701–708 doi:10.1111/cmi.12091
Firstpublishedonline14January2013
Microreview
Two unlike cousins: Candida albicans and C. glabrata
infection strategies
SaschaBrunke1,2andBernhardHube1,2,3* an extremely high mortality rate and fungi kill at least as
1DepartmentofMicrobialPathogenicityMechanisms, many people as tuberculosis or malaria (Brown etal.,
LeibnizInstituteforNaturalProductResearchand 2012).Overthelastdecades,theyhavebecomeamajor
InfectionBiology–HansKnoellInstituteJena(HKI), problem especially in the clinical setting (Perlroth etal.,
Beutenbergstrasse11a,07745Jena,Germany. 2007).CandidaalbicansandC.glabrata,forexample,are
2IntegratedResearchandTreatmentCenter,Sepsisund ubiquitous commensals of humans, and can be found
Sepsisfolgen,CenterforSepsisControlandCare especially in the oral cavity and the gastrointestinal tract
(CSCC),UniversitätsklinikumJena,Jena,Germany. of most healthy humans (Cole etal., 1996; Fidel etal.,
3FriedrichSchillerUniversity,Jena,Germany. 1999). On the other hand, they are also the most impor-
tant pathogenic yeasts. The majority of the population is
asymptomatically colonized by either of the two species,
Summary
or even both (Li etal., 2007b). However, under certain
CandidaalbicansandC.glabrataarethetwomost predisposing factors, such as treatment with antibiotics,
common pathogenic yeasts of humans, yet they diabetes, cancer, extreme age, immunosuppression,
are phylogenetically, genetically and phenotypi- intravenous catheters or long-term hospitalization, these
callyverydifferent.Inthisreview,wecompareand fungi can lead to superficial or even life-threatening
contrast the strategies of C.albicans and C.gla- systemic infections, with high morbidity and mortality
brata to attach to and invade into the host, obtain (Perlrothetal.,2007).AmongtheCandidaspecies,C.al-
nutrients and evade the host immune response. bicans and C.glabrata rank first and second in isolation
Although their strategies share some basic con- frequency,respectively,and,together,areresponsiblefor
cepts, they differ greatly in their outcome. While approximately 65%–75% of all systemic candidiasis, fol-
C.albicans follows an aggressive strategy to lowedbyC.parapsilosisandC.tropicalis(Perlrothetal.,
subvertthehostresponseandtoobtainnutrients 2007).
foritssurvival,C.glabrataseemstohaveevolved While C.albicans, C.parapsilosis and C.tropicalis are
a strategy which is based on stealth, evasion and relatively closely related members of the so-called CUG
persistence, without causing severe damage in clade (sharing a unique codon exchange from leucine to
murine models. However, both fungi are success- serine), C.glabrata is, as a Candida species, in fact a
ful as commensals and as pathogens of humans. ‘misnomer’: this yeast is actually much more closely
Understandingthesestrategieswillhelpinfinding related to the baker’s yeast Saccharomyces cerevisiae
novelwaystofightCandida,andfungalinfections than to C.albicans (Dujon etal., 2004), and this is
ingeneral. reflectedbyanumberofdifferences.Forexample,unlike
C.albicans, the progenitor of C.glabrata and S.cerevi-
siae experienced a whole-genome duplication event
Introduction
(Dujon etal., 2004).Additionally, C.albicans is a diploid,
Fungi infect billions of people every year, but still remain polymorphic fungus, switching readily from yeast to
largely under-appreciated as pathogens of humans hyphal(andpseudohyphal)growthandback.Incontrast,
(Brown etal., 2012). In fact, some fungal diseases have C.glabrata is strictly haploid and normally grows only in
theyeastform(Kauretal.,2005).Themorphologicalflex-
Received28September,2012;revised25October,2012;accepted
ibility of C.albicans seems to play fundamental roles in
29 October, 2012. *For correspondence. E-mail bernhard.hube@
hki-jena.de; Tel. (+49) (0)3641532 1401; Fax (+49) (0)3641532 several aspects of infection (Sudbery, 2011). In contrast,
0810. thepathogenicityofC.glabrataseemstobeindependent
Re-use of this article is permitted in accordance with the Terms
ofmorphology.Yet,bothfungiarecloselyassociatedwith
and Conditions set out at http://wileyonlinelibrary.com/onlineopen#
OnlineOpen_Terms humans,andsimilarlysuccessfulascommensalsandas
©2012BlackwellPublishingLtd
cellular microbiology
702 S.BrunkeandB.Hube
pathogens. But how similar are their commensal and types(deGrootetal.,2008;Desaietal.,2011;Kraneveld
pathogenicstrategies? etal., 2011).Additionally, it has been suggested that the
The phylogenetic tree, in which C.albicans (and the high expression heterogeneity of Epa1, and likely other
CUG clade) and C.glabrata are separated by several adhesins, leads to distinct subsets of Epa-expressing
non-pathogenicyeasts,stronglyimpliesthattheabilityto cellsinanypopulation,eachwithdifferentadhesionprop-
infect humans has evolved independently in the two erties(Halliwelletal.,2012).
species. Therefore, a closer look at the similarities and Auniquemechanismforsensingthehostenvironment
differences in the persistence and infection strategies of hasbeendescribedforthegenesencodingC.glabrata’s
C.albicans and C.glabrata may help to understand Epa proteins: their expression is regulated by Sir-
generalprinciplesoffungalinfections. complex-mediated transcriptional silencing (De Las
Penas etal., 2003; Castano etal., 2005). This system
requires NAD+ as a cofactor, and since C.glabrata is
Adhesion
auxotrophic for the NAD+ precursor nicotinic acid (NA),
For any successful commensal and pathogen, adhesion the silencing activity is indirectly influenced by external
tohostcellsisessential.Manybacteriapossesselaborate NAconcentrations.Becauseurineislowinnicotinicacid,
systems to detect the presence of the host by environ- EPAgenesarederepressedintheurinarytract,promoting
mentalcues,inordertoexpressspecificadhesins(Kline adhesion of C.glabrata in this niche (Domergue etal.,
etal., 2009).These factors in turn allow the microorgan- 2005). Interestingly, no systematic studies have so far
isms to attach firmly to a host cell, and help to prevent investigated whether the physiological body temperature
themfrombeingwashedaway.Adhesinsarealsocritical hassimilareffectsonthetranscriptionalprogramme,asis
fortheformationofbiofilms:BothC.albicansandC.gla- clearlythecaseinC.albicans.
brata can form biofilms on abiotic substrates, especially In summary, both fungi have independently evolved
medical devices such as catheters (Iraqui etal., 2005; specificadhesinswhichrelyondifferentcuestodetectthe
NobileandMitchell,2006). presence of the host. While the details differ, the basic
Candida albicans and C.glabrata have large protein principleisthesame–upondetectionofa‘host’environ-
familiesofadhesinsattheirdisposal:forC.albicans,the ment,adhesinsareexpressedtoattachtohostcells.
Als proteins with their Agglutinin-Like Sequences, are
crucial adhesins (Hoyer etal., 2008). Especially theAls3
Invasion
protein seems to play a vital role in adhesion, since its
deletion strongly reduces adhesion to epithelial cells After attachment, the next step in Candida pathogenesis
(Hoyeretal.,2008;Wächtleretal.,2012).Inaddition,this is invasion, normally into epithelial cell layers. For C.al-
protein is also important for iron acquisition from ferritin bicans,invasioncanoccurviatwomechanisms:induced
(Almeidaetal.,2008),formationofmixed-speciesbiofilms endocytosisbyhostcells,andactivepenetrationbyC.al-
(Silverman etal., 2010) and induction of endocytosis by bicanshyphae(Wächtleretal.,2011;2012).Als3isoneof
hostcells(Phanetal.,2007;Wächtleretal.,2012andsee the invasins which trigger endocytosis by inducing host
alsonextsection).AsAls3ishypha-associated(Argimon cytoskeletal rearrangements (Phan etal., 2007). This
etal.,2007),itisexpressedasthefungusformsfilaments, processdoesnotrequireviablefungianddoesnotcause
forexampleuponphysicalcontactwithhostcells,atbody damage per se, but seems to be important at the early
temperature and at ambient neutral pH. Expression stagesofinvasion(Wächtleretal.,2011;2012;Zhuetal.,
of another important adhesin, Hwp1, is likewise hypha- 2012). Yet, the dominant route of invasion is active pen-
associated(Staabetal.,1999),strengtheningtheconcept etrationofhostcells.Hyphaepenetratetissuebyacom-
ofinduced,hypha-associatedadhesion,asopposedtothe bination of physical forces exerted by the extending
‘ad hoc’ non-induced adhesion of attaching yeast cells filaments,thesecretionofhydrolyticenzymesandasyet
(WilsonandHube,2010;Wächtleretal.,2011). unknowndamagingfactors,whichfinallyleadstodisrup-
ThemainadhesinsofC.glabrata,theEpaproteins,are tion of host cell membranes (Wächtler etal., 2012).
related to the Flo proteins of S.cerevisiae, which are However, hyphae formation comes at a price: epithelial
responsibleforflocculationduringthebrewingprocess.In cells react to the hyphal surface, and to the inflicted
C.glabrata, this family of approximately 17–23 genes damage,bysecretingpro-inflammatorycytokines,demar-
(dependingontheisolate)allowsattachmenttoepithelial cating the transition to a pathogenic lifestyle (Schaller
cells (Cormack etal., 1999; Castano etal., 2005) and etal., 2002; Moyes etal., 2010; 2012). These events in
macrophages (Kuhn and Vyas, 2012). The predominant turnattractmacrophagesandneutrophils(Schalleretal.,
adhesin during in vitro interaction with epithelial cells is 2004),whichcanfightandkillinvadingC.albicans.
Epa1 (Cormack etal., 1999), whereas other Epa and Hypha-mediated penetration is widely assumed to
non-Epa adhesins can mediate attachment to other cell playanimportantroleingainingaccesstodeepertissue
©2012BlackwellPublishingLtd,CellularMicrobiology,15,701–708
CandidaalbicansandC.glabratainfectionstrategies 703
and the bloodstream. How can C.glabrata enter the process. It remains in a non-acidified organelle which
circulatory system without hyphae? A possible route to lacks typical lysosomal markers such as cathepsin D
reach the bloodstream is the accidental or iatrogenic (Seider etal., 2011). Similar to Histoplasma capsulatum
breach of natural barriers via trauma, catheters, surgery (Woods,2003;Seideretal.,2010)andbacterialikeMyco-
or parenteral nutrition (Perlroth etal., 2007). However, bacteriumspp.(deChastellier,2009),C.glabratanotonly
evenintheabsenceofsuchbreaches,C.glabratayeasts survives, but replicates inside the phagosome until the
invade into deeper tissues and readily disseminate in a phagocytefinallybursts(Kauretal.,2007;Roetzeretal.,
chicken embryo model of fungal infections (Jacobsen 2010; Seider etal., 2011). Other survival strategies
etal., 2011). The mode of this invasion is unclear, include expression of a highly active catalase (Cuellar-
although S.cerevisiae cells are known to form agar- Cruz etal., 2008) and pigment production, which may
invasivepseudohyphalunderinvitrostarvationconditions counteract the oxidative burst of phagocytes (Brunke
(Gimeno etal., 1992) and one report even described etal.,2010).Inaddition,thecytokineresponseofmacro-
pseudohyphaeofC.glabratainvitro(CsankandHaynes, phages to C.glabrata in vitro is much lower than during
2000).However,invivo,itmayrelyonendocytosis,inlieu interactionwithC.albicans(Seideretal.,2011).Consist-
ofactivepenetration,withclosetonohostcelldamage(Li ently, murine and chicken embryo infections with C.gla-
etal., 2007a). Most likely because of low host damage, brata lead only to a transient pro-inflammatory cytokine
the cytokine profile of epithelia infected with C.glabrata response,andonlyaminorinfluxofimmuneeffectorcells
differsdramaticallyfromthatofC.albicans-infectedcells: (Jacobsenetal.,2010;2011).Duringinvitroexperiments,
C.glabrata induces more GM-CSF than C.albicans, but C.albicansalsoappearstodelayphagosomematuration
nearlynoneoftheotherinflammatorycytokineslikeIL-1a and to induce recycling of late maturation markers like
or Il-8 (Schaller etal., 2002; Li etal., 2007a). This is in LAMP-1(Fernández-Arenasetal.,2009).However,soon
good agreement with the cytokine pattern observed aftertheseinitialevents,C.albicansstartstoformhyphae
during in vivo murine infections (Jacobsen etal., 2010). which disrupt the macrophage membranes, effectively
Consequently,strongneutrophilinfiltrationischaracteris- killing the phagocyte and allowing the fungus to rapidly
ticforC.albicansinfections,whileC.glabrataeitherdoes escape(Loetal.,1997;McKenzieetal.,2010).Themac-
not stimulate or is able to suppress neutrophil attraction rophagephagosomeisanutrient-poorandharmfulenvi-
andisratherassociatedwithmononuclearcells(Westwa- ronment. Escape from phagocytes may therefore be a
teretal.,2007;Jacobsenetal.,2010).Overall,thepres- strategy of C.albicans to quickly escape this detrimental
ence of hyphae and host cell damage in C.albicans environment (Hummert etal., 2010), while C.glabrata
infections leads to a stronger pro-inflammatory cytokine depends on fungal autophagy to survive inside macro-
responsethaninC.glabratainfections. phages (Roetzer etal., 2010). Interestingly, even
autophagy-deficient mutants of C.albicans can still
escapethephagocytesandsubsequentlygainaccessto
Interactionwithimmunecells
the external nutrients (Palmer etal., 2007). The in vitro
Macrophages are part of the first line of defence by the observations of a quick escape from macrophages by
innate immune system. These phagocytes recognize C.albicans have been challenged recently by experi-
invading fungi in the tissue via a subset of their PRRs ments in live zebrafish. In this model, C.albicans
(pattern recognition receptors) which specifically bind to remainedviableafterphagocytosis,buthyphaeformation
fungal PAMPs (pathogen associated molecular pattern), was not observed (Brothers etal., 2011). How far this
such as b-glucan (Taylor etal., 2007), mannan or chitin reflects the situation in the mammalian host, however, is
(van der Meer etal., 2010; Mora-Montes etal., 2011). largely unknown, especially since mammals differ from
Interestingly, C.glabrata is recognized and ingested by the ectothermic zebrafish model by their high body tem-
macrophagesatamuchhigherratethanC.albicans,and perature – an important hypha-inducing factor. Addition-
C.albicans yeasts more than hyphae (Keppler-Ross ally,arecentstudyevenreportedararenon-lyticescape
etal., 2010). These preferences seem to be mannan ofC.albicansyeastscellsfrommacrophages(Bainetal.,
dependent,butindependentofglucanorchitin(Keppler- 2012),inamannerreminiscentoftheprocessdescribed
Ross etal., 2010). Without intervention by the phagocy- for Cryptococcus neoformans (Alvarez and Casadevall,
tosed microbe, the phagosome normally matures via a 2006).Thus,thepreciseinvivoescapestrategiesofC.al-
seriesoffusionandfissionevents,andthepathogensare bicansfromphagocytesrequirefurtherresearch.
killed in the matured phagolysosome. Furthermore, by
releasingcytokinesuponrecognitionofpathogens,mac-
Nutrientacquisitionwithinthehost
rophageshelptoorchestratetheimmuneresponses.
However, when C.glabrata is internalized by macro- During infection, a molecular tug-of-war takes place
phages, it modifies the normal phagosome maturation betweenthehost,whichtriestorestrictaccesstoessen-
©2012BlackwellPublishingLtd,CellularMicrobiology,15,701–708
704 S.BrunkeandB.Hube
tial nutrients, and the pathogen, which needs these itcanbindhydroxamate-typexenosiderophoresoffungal
nutrients to survive and multiply. Acquisition of nutrients origin, like ferrichrome, ferrirubin or coprogen, but unlike
by the fungus is therefore central to establishing and C.albicansnotbacterialsiderophores(NevittandThiele,
maintaining infection. Interestingly, due to its frequent 2011).Thisbindingsignificantlyincreasesfitnessandsur-
gene losses (Dujon etal., 2004), C.glabrata lacks many vivalinsidemacrophagesaftersubsequentphagocytosis
ofthemetabolicpathwaysknowninotheryeasts,includ- (NevittandThiele,2011).Therefore,C.glabrata’sinvivo
ing S.cerevisiae and C.albicans. It cannot catabolize choiceofironsourceswouldappeartobelimitedincom-
galactose (due to its loss of genes GAL1, 7, 10) and parisonwithC.albicans.
allantoin (DAL1–4, 7), and is auxotrophic for pyridoxine Zinc, a central cofactor for many proteins, is also
(SNO1, 2, 3), nicotinic acid (BNA1–6) and thiamine activelylimitedbythehostduringinfections(Corbinetal.,
(Dujon etal., 2004; Wong and Wolfe, 2005). These 2008), but it can be scavenged by C.albicans via a
restrictionsmustbeovercomeinthespecifichostniches recently discovered ‘zincophore’ system using Pra1
conquered by C.glabrata. In contrast, C.albicans does (Citiulo etal., 2012). This protein is secreted, binds zinc
not have any known auxotrophies, can metabolize a anddeliversitbacktothepathogeninamannerreminis-
broadrangeofsugarsandcanuseallaminoacidsassole cent of the iron-carrying siderophores. C.glabrata is
nitrogensources(Odds,1988;Kauretal.,2005;andown missing both Pra1 and its proposed binding partner, the
observations).Inaddition,C.albicanspossessesseveral high-affinity zinc transporter Zrt1 (Citiulo etal., 2012).
families of secreted hydrolases and transmembrane Possibly,C.glabrataacquiresZnviaitstwohomologues
transporters with central roles in virulence (Butler etal., of the low-affinity S.cerevisiae zinc transporter Zrt2, but
2009). Secreted aspartic proteases (Saps), for example, this still requires experimental confirmation. In addition,
have the potential to destroy host tissue and liberate othermicronutrientslikemanganese(Kehl-FieandSkaar,
oligopeptidesandaminoacids,whicharetakenupbythe 2010)orcopper(HodgkinsonandPetris,2012)mayplay
fungus via oligopeptide and amino acid transportes important roles in host–pathogen interactions, and their
(Naglik etal., 2004). Contrarily, C.glabrata exhibits low uptake systems in Candida species are still largely
extracellularproteaseactivityinvitro(Kauretal.,2005). unknown.
Micronutrientsareanotherprerequisiteforasuccessful Itseems,therefore,thatthehighmetabolicflexibilityof
infection.Especiallymetalslikeironandzincaresubject C.albicansmaybepartofitsinfectionstrategy,enabling
to a process called ‘nutritional immunity’, where the host thisfungustosurviveandgrowinthemanydifferentand
actively sequesters these elements from invading micro- changing host niches it encounters. C.glabrata, on the
organisms(HoodandSkaar,2012).Ironlevelsinhuman other hand, appears more specialized in its metabolic
serum are held as low as 10-24M, severely restricting its requirement, possibly requiring a more stable environ-
availability to pathogens. To counteract this limitation, ment,wheretheseneedsaremet.
C.albicans has a plethora of iron acquisition systems
at its disposal (Almeida etal., 2009): It can utilize
Conclusion
siderophoresfromothermicroorganismswithoutproduc-
ingitsown(viaSit1/Arn1,Heymannetal.,2002),andbind The problems and obstacles faced by both C.albicans
host transferrin (via an unknown receptor, Knight etal., and C.glabrata during infections are essentially the
2005)andferritin(viaAls3,Almeidaetal.,2008).Inaddi- same, but the solutions employed differ in many ways
tion,C.albicanscanexpresshaemolysinsthatdisruptred (Fig.1):overall,C.glabrataseemstofollowastrategyof
blood cells (Watanabe etal., 1999) and then bind and stealth and concealment in infection. It does not cause
utilize haemoglobin via the Rbt5/Hmx1 system (Pendrak extensiveepithelialdamage,probablyduetoitslackofan
etal.,2004;WeissmanandKornitzer,2004).Freeiron,if invasive growth form. It does not elicit a strong immune
available, is taken up via the reductive pathway with its response in murine models or in in vitro reconstituted
largegenefamiliesofreductases,oxidasesandironper- human epithelia, and it can reside within macrophages
meases (Almeida etal., 2009). Together, these systems without immediately destroying them. When it comes to
enableC.albicanstoeffectivelyusenearlyallnaturaliron nutrient supply in the host, C.glabrata relies on
sourcesbothofthehostduringinfectionandofsurround- autophagy and some so far uncharacterized nutrient
ingmicrobesduringcommensalgrowth. uptakemechanisms,butitwouldnotappeartoelicitrapid
Candida glabrata, on the other hand, has no known tissue damage to release nutrients from host cells.
receptors for haem (Nevitt and Thiele, 2011); however, Genomically, C.glabrata displays some of the hallmarks
haemolysin expression has been reported (Luo etal., ofaspecializedcommensalorpathogenofhumans.The
2004). In addition, although the reductive pathway is loss of many metabolic pathways is indicative of a more
present, C.glabrata is not known to use host ferritin or stable environment than the one faced by C.albicans.
transferrin as iron sources. Interestingly, like C.albicans, Although it is unclear how far these (mostly) in vitro
©2012BlackwellPublishingLtd,CellularMicrobiology,15,701–708
CandidaalbicansandC.glabratainfectionstrategies 705
Fig.1. SchematicoverviewofthetwodifferentinfectionstrategiesofC.albicansandC.glabrata.
A.C.albicansformshyphaeandaggressivelydestroystissue,elicitingastrongimmuneresponse.
B.ManyaspectsofC.glabratapathogenicityarestillunknown,liketheprecisemechanismofinvasion.Activehosttissuedamageislow,asis
theimmuneresponse.Foradetaileddescriptionoftheindividualsteps,seetherelatedsectionsinthetext.
observations translate into infections of the human host, (Reddingetal.,2002;Cocoetal.,2008),andC.glabrata
C.glabratacanpersistwithintheinternalorgansofmice may exploit the tissue destruction caused by C.albicans
forasurprisinglylongtimewithoutanyclinicalsymptoms. togainnutrients,andpossiblyeventoaccesstheblood-
A possible scenario is that C.glabrata attracts macro- stream. Moreover, this concept of C.albicans paving the
phages, which it subverts to use as a ‘trojan horse’, to way for C.glabrata may have serious clinical conse-
hide from immune surveillance and to spread to the quences: once C.glabrata reaches internal organs, its
organs, analogous maybe to the strategy employed by inherently high resistance to many commonly used anti-
C.neoformans(Charlieretal.,2009). fungalsmakestreatmentmoreproblematic.
Candidaalbicans,ontheotherhand,followsastrategy Thesestrategiesmaybeover-simplifiedforthepurpose
which can be described as ‘shock and awe’when it has of this review, and many nuances were necessarily left
changedfromcommensaltopathogen.Itactivelyinvades out.However,muchoftheevidenceshowsthatthesetwo
epithelia when the circumstances permit and elicits fungiuseverydifferentpathwaystoobtainthesamegoal
strongerimmuneresponses,whichitseemstocounteract –tosurviveandproliferateduringinfectionofthehuman
inmanycases.Macro-andmicronutrientsfromdamaged host.Understandingthesestrategieswillhopefullyhelpin
host tissue are taken up by a broad range of acquisition findingnovelwaystofightCandida,andfungalinfections
systems, and defending macrophages may be killed by ingeneral.
formation of hyphae. Tissue damage by the fungus and
theactivatedimmunesystemcanleadtoseveredisease,
Acknowledgements
and death. In some cases, C.glabrata may benefit
from this strategy of C.albicans. In oral candidiosis, OurownresearchissupportedbytheGermanFederalMinistryof
for example, co-infections by both fungi are common EducationandResearch(BMBF:ERANetPathoGenoMicsCan-
©2012BlackwellPublishingLtd,CellularMicrobiology,15,701–708
706 S.BrunkeandB.Hube
diCol,0315901B;CenterforSepsisControlandCare–CSCC, zincviaPra1duringendothelialinvasion.PLoSPathog8:
FKZ 01EO1002), the Deutsche Forschungsgemeinschaft (DFG e1002777.
Hu 528/14, 15, 16 and 17; including the Priority Program Coco, B.J., Bagg, J., Cross, L.J., Jose, A., Cross, J.,
SPP1580 ‘Intracellular compartments as places of pathogen– and Ramage, G. (2008) Mixed Candida albicans and
host-interactions’), the European Union (FinSysB MCRTN Candida glabrata populations associated with the patho-
FP7-214004),BayerVitalandtheJenagraduateschools‘Inter- genesis of denture stomatitis. Oral Microbiol Immunol 23:
nationalLeibnizResearchSchoolforMicrobialandBiomolecular 377–383.
Interactions’(ILRS)andthe‘JenaSchoolforMicrobialCommu- Cole,G.T.,Halawa,A.A.,andAnaissie,E.J.(1996)Therole
nication’ (JSMC). We thank Katja Seider, Ilse Jacobsen and of the gastrointestinal tract in hematogenous candidiasis:
DuncanWilsonforcriticalreadingofthemanuscript. from the laboratory to the bedside. Clin Infect Dis 22
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Corbin, B.D., Seeley, E.H., Raab, A., Feldmann, J., Miller,
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