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Surface Glycans of Candida Albicans and Other Pathogenic Fungi Physiological Roles, Clinical Uses, And Experimental Challenges - Clin. Microbiol. Rev.-2004-Masuoka-281-310

Surface Glycans of Candida Albicans and Other Pathogenic Fungi Physiological Roles, Clinical Uses, And Experimental Challenges - Clin. Microbiol. Rev.-2004-Masuoka-281-310

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10.1128/CMR.17.2.281-310.2004.2004, 17(2):281. DOI:
Clin. Microbiol. Rev.
James Masuoka
ChallengesRoles, Clinical Uses, and ExperimentalOther Pathogenic Fungi: Physiologicaland
Candida albicans 
Surface Glycans of
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C
LINICAL 
M
ICROBIOLOGY
R
EVIEWS
, Apr. 2004, p. 281310 Vol. 17, No. 20893-8512/04/$08.00
ϩ
0 DOI: 10.1128/CMR.17.2.281–310.2004Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Surface Glycans of 
Candida albicans
and Other Pathogenic Fungi:Physiological Roles, Clinical Uses, and Experimental Challenges
James Masuoka*
 Department of Pathology, University of Virginia, Charlottesville, Virginia 22908-0904
INTRODUCTION.......................................................................................................................................................281GLYCANS IN THE
CANDIDA
CELL WALL.........................................................................................................282Basic Components ..................................................................................................................................................282Glucan ..................................................................................................................................................................283Chitin....................................................................................................................................................................283Mannan................................................................................................................................................................284Sialic acids...........................................................................................................................................................285Combination To Form the Cell Wall...................................................................................................................287FUNGAL GLYCANS IN PATHOGENESIS AND HOST RESPONSE...............................................................288Protein Folding and Tertiary Structure ..............................................................................................................288 Adhesion...................................................................................................................................................................288 Adhesion to host components ...........................................................................................................................288(i)
-1,2-Mannan ............................................................................................................................................289(ii) Acid-stable mannan.................................................................................................................................289(iii) O-linked glycans......................................................................................................................................290 Adhesion to other members of the microflora................................................................................................290Immune Cell Receptors and Interactions ...........................................................................................................292Glycan binding to and activation of immune cells ........................................................................................294(i) Mannan.......................................................................................................................................................294(ii) Chitin.........................................................................................................................................................294(iii) Glucan ......................................................................................................................................................295Glycan influence on cytokine production ........................................................................................................296(i) Mannan.......................................................................................................................................................296(ii) Glucan........................................................................................................................................................296Recognition by antibodies..................................................................................................................................297DIAGNOSTICS AND THERAPEUTICS.................................................................................................................298Diagnostics...............................................................................................................................................................298Mannan assays....................................................................................................................................................298Glucan assays......................................................................................................................................................299Therapeutics............................................................................................................................................................299ISSUES IN CARBOHYDRATE CHEMISTRY.......................................................................................................300Detection and Separations.....................................................................................................................................300Complexity and Characterization.........................................................................................................................302CONCLUDING REMARKS......................................................................................................................................303 ACKNOWLEDGMENTS ...........................................................................................................................................304REFERENCES............................................................................................................................................................304INTRODUCTION
Infections by pathogenic fungi, particularly
Candida
species,are both widespread and increasing in frequency (68, 276).Oral colonization by
Candida albicans
has been reported at17.7% in the healthy population (40). Among hospitalizedpatients, oral carriage of 
Candida albicans
rises to 40.6%.Healthy, asymptomatic women demonstrate an incidence of  vaginal colonization by
Candida
of 15 to 20%. This percentagerises to 20 to 40% in healthy pregnant women and to 40 to 60%in human immunodeficiency virus-infected pregnant women(26, 209, 254, 273). Hospitals in the United States participatingin the National Nosocomial Infection Survey System reporteda nosocomial fungal infection frequency of 3.8 per 1,000 dis-charges in 1990, an increase from 2.0 per 1,000 discharges in1980 (17).
Candida
species accounted for 78.3% of all suchnosocomial fungal infections, followed by
Torulopsis
(now
Candida
)
glabrata
and
Aspergillus
species.
C. albicans
was themost frequently isolated of all the
Candida
species (17, 219).Furthermore, a European study reported that fungal species ingeneral accounted for 17.1% of intensive care unit-acquiredinfections (306).Using the National Nosocomial Infection Survey (1980 to1990) data, Jarvis and Martone (131) reported that
Candida
species accounted for 9.4% of nosocomial urinary tract infec-tions, 10.1% of nosocomial infections in adult and pediatricintensive care units, and 7.8% of nosocomial bloodstream in-fections. In 1990, fungi as a whole accounted for 10% of all
* Mailing address: James Masuoka, Department of Pathology, Uni- versity of Virginia Health System, P.O. Box 800904, Charlottesville,VA 22908-0904. Phone: (434) 243-2744. Fax: (434) 924-2151. E-mail: jm2n@virginia.edu.281
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nosocomial bloodstream infections (17). Ten years later, therates of bloodstream infections due to
Candida
are still rising, with half of these candidemias due to
C. albicans
(230). Morerecently, other
Candida
species
such as
C. glabrata
,
C. tropi- calis
, and
C. dubliniensis
have been isolated with increasingfrequency (220). A study carried out by
 ve university hospitalsin the Netherlands also reported increased fungemia rates.Between 1987 and 1995, episodes of fungal bloodstream infec-tions rose from 0.37 to 0.76 per 10,000 patient days. Of theseinfections, 93% were due to
Candida
species while 7% weredue to
Cryptococcus
species (307).In addition to the observed increases in incidence, fungalinfections continue to be a serious clinical problem with re-spect to increased morbidity and mortality (194, 314; see alsoreference 219 and references therein). An analysis of recordsfrom the National Center of Health Statistics indicated thatmycoses ranked 10th among the underlying causes of death inthe United States in 1980 but that by 1997 this rank had risento 7th (193). Increased morbidity due to nosocomial fungalinfections also takes a heavy toll, resulting in longer hospitalstays (49, 178, 314) and higher patient care costs (91, 234, 285).The increasing incidence of fungal infections has, to a cer-tain degree, coincided with the incredible medical advances of the last few years. Life-prolonging technologies, although wel-comed by medicine and those it cares for, have unfortunatelycreated numerous opportunities for emerging fungal infec-tions. The rising number of immunocompromised patients, whether through immunosuppressive therapy, AIDS, or otherailments, the prophylactic use of antimicrobics, and the in-creasing number of indwelling catheters and prosthetic devicesseen among patients all unwittingly subject patients to thethreat of invasive disease (68). Patients with central intrave-nous IV catheters were over three times more likely to havebloodstream infections than patients without such catheters(17). Patients undergoing orthotopic liver transplantationdemonstrated an incidence of invasive fungal infection of 5 to42%, with
Candida
species being the most commonly isolatedorganism, followed by
Aspergillus
species (54). A study of hearttransplant patients reported that while fungal infections ac-counted for only 7% of all infections, they were associated withthe highest (36%) mortality (194). Taken together, these clin-ical observations strongly reinforce the necessity for under-standing the relationship between fungus and host.The interaction between fungus and patient occurs
rst atthe level of the cell wall (35). The cell wall of most fungi iscomposed of glycoproteins embedded within a polysaccharidematrix or scaffolding. Additionally, some fungal species pro-duce a polysaccharide capsule that surrounds the cell wall (e.g.the glucuronoxylomannan capsule produced by
Cryptococcus neoformans
[221]). It is therefore possible, and even likely, thatcarbohydrate, not DNA or RNA and perhaps not even protein,is the
rst component to contact host tissue. Thus, character-ization of these exterior carbohydrate groups could lead to (i)a better understanding of fungal adhesion and mechanisms by which fungi avoid the host immune system, (ii) proposals forcountering this avoidance so as to enhance the immune re-sponse, and (iii) the development of diagnostic tests based onidenti
cation of carbohydrate components. The utility of cell wall and cell surface carbohydrate groups has been shown inother areas of clinical microbiology (e.g.,
Mycobacterium
) (23).Fungal cell surface carbohydrates also play an important rolein industry (132, 135) and in plant and nonhuman animalfungal pathogenesis.The purpose of this review is to bridge the areas of fungalpathogenesis and glycobiology. To this end, the manuscript isdivided into three major sections. First, a brief introduction tothe carbohydrate components of the fungal cell wall and howthey are assembled is provided. Second, relevant studies wherecarbohydrates have been shown to play a role in infection,function in diagnostic assays, and act as therapeutic agents arediscussed. The
nal section is a discussion of the practicalissues and dif 
culties that arise when working with microbialcarbohydrates.This review is limited in scope in two ways. First, althoughthere is an extensive body of literature describing the variousstructures and pathways by which microorganisms interact withhost species, the focus of this review is fungal glycobiology.Therefore, discussion is limited to the polysaccharide compo-nents of the fungal cell wall and does not include more generalfungal cell fractions, fungal proteins and lipids, or elements of the host cells. In addition, examination of the
C. albicans
lit-erature illustrates the need for both careful identi
cation of fraction components and strategies for demonstrating that car-bohydrate, rather than protein or lipid, is responsible for theobserved effect. For example, while
C. albicans
mannan (de-
ned below) is found only as a glycoconjugate with protein orlipid, many pathogenesis studies use the term
mannan
torefer globally to mannoprotein or similar glycoconjugate frac-tions.Second,
C. albicans
will serve as the example organism forrelating glycobiology to clinical microbiology. Studies describ-ing the role of carbohydrate groups in pathogenesis have beencarried out mainly with
C. albicans
; therefore, the review like- wise focuses on this organism. A review by Nelson et al. (202)focused on
Candida
mannan and issues of mannan chemistry,immune suppressive effects, and mechanisms of action. Thisreview expands on their discussion to include glucans andrelevant mannan results reported since the publication of theprevious review. Although the focus is
C. albicans
, it should beremembered that carbohydrates, as polysaccharides or compo-nents of glycoproteins, play a role in the pathogenesis anddiagnosis of other fungal species such as
Cryptococcus neofor- mans
,
Aspergillus fumigatus
,
Kluyveromyces lactis
, and
Paracoc- cidioides brasilienis.
Where appropriate, selected results fromstudies of these species are included in the discussion.
GLYCANS IN THE
CANDIDA
CELL WALLBasic Components
Three types of monosaccharides form carbohydrate chains,or glycans, within the
Candida
and
Saccharomyces
cell wall:
D
-glucose (Glc),
-acetyl-
D
-glucosamine (GlcNAc), and
D
-man-nose (Man) (Fig. 1). A comparison of the cell envelope glycansfrom some pathogenic fungi is presented in Table 1, and amore general discussion of fungal cell wall composition, struc-ture, and assembly can be found in reference 242. Recently,there have been several reports of sialic acid as a constituent of the
Candida
cell wall, presumably as terminal residues of gly-coprotein glycans (2, 140, 272, 308). These reports are remark-
282 MASUOKA C
LIN
. M
ICROBIOL 
. R
EV
.
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