Candida Albicans: Pathogenesis, Immunity and Host Defence

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factors. This issue is discussed by Kullberg and

Anaissie, who review the benefic ial effect of

G-CSF, TNFa, ILl, IL12 and IFNyadministration or

IL4 neutralization in experimental models of fungal

infections. In patients with qualitat ive or quantita-

tive defects in phagocyte functions, IFNy, G-CSF

and GM-CSF prove to have therapeutic potential

when given prophylactically or during established

infection. Cytokines and growth factors may also

augment the antifunga l activities of leukocytes

from HIV-infected indiv iduals , as discussed by

Levitz in his chapter. He points out that predisposi-

tion of HIV-infected individuals to mycoses is a

result of many factors, including mononuclear and

polymorphonuclear phagocyte dysfunctions resul-

ting in impaired antifungal activity and cytokine

secretion. However, the find ing that fungi and fun-

gal products stimulate HIV replication in latently

infected cells underscores the complexity of host-

fungal interactions in HIV infection.

This research Forum was conducted under the auspices of the Italian Research Program on AIDS (Opportunistic

Infections and Tuberculosis Project).

Candida albicans: pathogenesis, immunity and host defence

R.B. Ashman

Oral Biology and Pathology, School of Dentistry, University of Queensland, Brisbane Old. 4072

Introduction

Infections with the yeast Candida albicans

present a significant and increasing clinical problem.

Oral and vaginal candid is are common in the gen-

eral population, but are seen most frequently, and in

their most severe form, in individuals with defects in

the cell-mediated immune response. In contrast,

systemic or disseminated candidiasis is usually a

disease of debilitated or immunocompromised

patients in the hospital environment.

There are many different models for the study of

C. albicans infections, some focussing on the muco-

sal, and others on the systemic infection. The mouse

has been the most common experimental animal,

because the lesions induced by intravenous chal-

lenge closely resemble, in nature and distribution,

those seen n the human disease Louria et al., 1963 ;

Papadimitriou and Ashman, 1986). However, there

are considerable variations among inbred strains in

the severity and other measures of infection. This

paper will summarize these differences, and con-

sider their relationship to mechanisms of host

defence and the induction of adaptive immunity.

Genetics of susceptibility and resistance

In determining patterns of susceptibility and

resistance n different inbred strains, the necessity of

evaluating and comparing different measures of

infection has become apparent. Not only do these

different criteria reflect different aspects of the

host/yeast interaction, but there is no simple rela-

tionship between them, and they cannot be regarded

as interchangeable. Mortality, which is often

regarded as

an

index of overall susceptibility,

shows a general correlation with the magnitude of

the fungal burden in the kidney (Marquis et al.,

1988; Salvin and Neta, 1983) ; but the latter, which

reflects the efficiency of the hosts candidacidal or

candidastatic effector mechanisms, is relevant only

as ong as the tolerance to yeast colonization of par-

ticular organ systems is not exceeded. In contrast,

the severity of

lesions in

the

tissues represents the

resultant of the interaction between the proliferating

yeast and the host responseagainst it, at a particular

point in time.

The significance of these distinctions lies in the

insights they provide into the patterns of susceptibil-

Received April 9, 1998.


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73rd FORUM IN IMMUNOLOGY

ity to systemic challenge seen in various inbred

strains. In general, indices such as mortality and time

to death bear no relationship to the strain distribution

of known reference genes, such as those within the

major histocompatibility complex (MHC), although

mice deficient in the fifth component of complement

(C.5) arc significantly more susceptible to lethal chal-

lenge than U-sufficient mice (Hector

et al.,

1982;

Morelli and Rosenberg, 1971). However, histological

and quantitative studies have revealed the existence

of at least two host variables that complicate interpre-

tation of the response. The firs t of these is regulated

by a Mendelian-type gene, now named CargI (Ash-

man

et

al., 1997), that determines whether the extent

of tissue destruction after systemic infection is mild,

as in BALB/c mice, or severe, as in the CBA/&I-I

strain. There is also evidence for the existence of a

second level of genetic control, that influences the

susceptibility of the kidney [Ashman, unpublished].

Allocation of presumptive resistant and suscep-

tible alleles of these genes among various inbred

strains gives an excellent correlation with the various

measures of infection.

It can be seen (table I) that possession of the sus-

ceptible allele of the Cargl gene correlates not only

with severe tissue damage, but also with a moderate

increase in the fungal burden in the kidney. It is

assumed that this latter leads to a higher proportion of

animals that develop acute pyelonephritis, with a

consequent increase in mortality. Cur-g1 in mice does

not segregate with MI-K type (Ashman and Papadi-

mitriou, 1989). and by implication is not dependent

on the function of T lymphocytes. This conclusion is

supported by the observation that nude mice bred on

either BALB or CBA backgrounds show similar pat-

terns of tissue damage to their respective heterozy-

gous littermates (Fulurija et al., 1997). Preliminary

evidence suggests that this gene exerts its function

via the properties of a bone-marrow-derived cell

(Ashman and Papadimitriou, 1992), most probably o f

neutrophil lineage. The second gene, Carg; was first

identified in CS-sufficient C57/L mice (Ashman

et

al., 1997). In these animals, the susceptible allele

causes a marked increase in the severity of tissue

damage, but only a slight increase in the fungal bur-

den, relative to C57BU6 mice (Ashman, unpublished

data). However, in CS-deficient animals,

Carg2

appears to interact with the haemolytic complement

gene (Hc) to increase dramatically both kidney colon-

ization and mortality. The chromosomal localization

of

Cargl

and

Carg2

has not yet been definitively

established, so it is not clear whether the latter is

closely linked to Hc, or in what way the two genes

(or their products) interact.

What then, are the implications of the above for

mechanisms of host resistance? An important consid-

eration is whether effector mechanisms identified in

one infected organ or anatomical region are specific

to that particular site, or common to all. The evidence

favours site-specific responses. Variations in the can-

didacidal activity of macrophages derived from dif-

ferent anatomical districts have been documented

(Decker et al., 1986), and production of tumour

necrosis factor-a (TNF@ by such cells may be influ-

enced by the morphological form (yeast or hyphae)

of the fungus to which they are exposed (Blasi et al.,

1994). In addition, specific organs may be protected

by different mixes of effector cell types. For exam-

ple, depletion of neutrophils from inbred mice dra-

matically exacerbated the severity of infections in the

heart and the kidney, but had only a minor effect on

the fungal burden and severity of lesions in the brain

(Ful~ja

et al.,

1996). Interestingly, depletion of neu-

trophils from CS-deficient mice resulted in the devel-

opment of lesions in the liver and spleen - Iesions

that were not present in the CS-sufficient strains. This

Table I. The influence of different alleles of the C. albicuns resistance genes (Cargl and Carg2) and haemo-

lytic complement (Hc) on various measures of infection with C. albicans in inbred strains of mice.

Mouse

strain

H-2

type

Tissue

damage Cargl

Kidney

colonization Carg2 Hc Mortality

ALI

AKR

BALB/c

C57Bl/6

c57iL

CBA/CaH

C3H

DBA/l

DBA/2

Mild

Severe

Mild

Mild

Mild

Severe

Mild

Mild

Mild

High

Moderate

Low

Low

Low-moderate

Moderate

Low

LOW

High

High

Low-moderate

Low

Low

NT

Low-moderate

Low

Low

High

NT=not tested. D


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IMMUNITY TO FUNGI 283

suggests that C5 may exert more pervasive effects

than has hitherto been recognized.

These results emphasize that the pathogenesis of

the infection in any particular anatomical region is

dependent on numerous host defence mechanisms,

but of more importance, the dominant effector

mechanism may vary from organ to organ within

any specific inbred strain. The precise effector

systems recruited may be determined by the genetic

context within which the infection is established.

Pathogenesis and host resistance

Phagocytic cells represent an important component

of host effector mechanisms against systemic infec-

tion with C. albicans. Polymorphonuclear leucocytes

represent the first line of defence ; however, macro-

phages, as well as specific immune responses, have

been implicated in clearance of the fungal burden

after primary systemic infection. The relative contri-

butions of innate and adaptive immunity have been

reviewed elsewhere (Ashman and Papadimitriou,

1995) - the purpose here is to propose that certain

paradoxes and confl icts in the immunobiology of the

disease can best be resolved by reference to advances

in understanding the pathogenesis of the infection.

Role of T cells

There is now a large body of experimental data

demonstrating the involvement of T-helper-derived

cytokines in susceptibility and resistance to systemic

C.

albicans

infection. The experimental models have

utilized carefully defined combinations of yeasts

(attenuated and virulent) and inbred strains to pro-

duce infections that either resolve, with the develop

ment of resistance to re-infection (healing), or that

lead to chronic disease and death (non-healing)

(Mencacci et al., 1995).

Cytokine production in healing combinations is

associated with the generation of a T helper type 1

(lh,) cytokine profile by CD4+ spleen cells in vitro,

whereas the Th, profile is seen in lymphocytes from

animals that develop chronic disease. A causative

role for these cytokines in the pathogenesis of the

disease was demonstrated by neutralization with

monoclonal antibodies, or by blocking with the

appropriate soluble receptor. Administration of a

monoclonal antibody specific for interferon-y (IFNy)

to mice with a healing infection changed the cyto-

kine profile from a Th,-type, that was associated

with protection, to a non-protective Th,-type

response (Romani et al., 1992a). Conversely, when

mice with non-healing infections were treated with

monoclonal antisera specific for either interleukin-4

(IL4) (Romaui et aZ., 1992~) or IL10 (Romani et al.,

1994), survival was enhanced. Yeasts were cleared

from infected organs, and splenocytes exhibited

strong Th, cytokine responses. Comparable results

were obtamed by treatment with recombinant solu-

ble IL4 receptor (Puccetti et al., 1994).

Recent results, however, suggest that this elegant

model may not be universally applicable. Studies of

systemic infection in IFNy knockout mice (Qian and

Cutler, 1997) showed that survival of the genetically

modified mice was not impaired, and colony counts

in liver, spleen and kidneys were not significantly

different from those in wild-type mice. Similarly,

analyses of cytokine mRNA profiles in the brains of

mice that developed severe and mild tissue damage

after systemic infection failed to demonstrate any

bias towards either a Th i or Th, type (Ashman er al.,

1995). These latter results are consistent with other

demonstrations that differences in the severity of tis-

sue destruction after systemic infection in inbred

strains are independent of T-cell function (Ashman

and Papadimitriou, 1987,1992; Fulurija et al., 1997).

It can be argued that strain-dependent changes in

the severity of sublethal infections do not directly

address the function of T lymphocytes in acute

lethal disease. However, there is considerable addi-

tional evidence suggesting that cell-mediated immu-

nity has little or no role in protection from mortality

and clearance of yeasts from infected tissues.

Candidiasis in immunodeficient mice

The gold standard for the involvement of T cells

in host resistance to infectious agents is a significant

increase in the infectious burden and/or a marked

exacerbation of tissue damage in the absence of the

appropriate effector T-lymphocyte population. By

these criteria, studies in immunodeficient and T-cell-

depleted mice have failed to provide convincing evi-

dence that cell-mediated immune responses are

required for clearance of the yeast from the tissues

of mice after intravenous challenge.

Several independent groups have shown that

systemic infections in nude mice are less severe than

in heterozygous littermates (Cutler, 1976; Fulurija et

al., 1997 ; Miyake er al., 1977 ; Rogers et al., 1976).

Similarly, the course and severity of systemic infec-

tion in scid mutant mice were indistinguishable from

those in heterozygous controls (Mahanty et al., 1988>,

with the exception of the kidney, in which the fungal

burden was significantly reduced. The failure to detect

a reduced efficiency of clearance of the yeast as a con-

sequence of defective cell-mediated immunity in these

mice has usually been attributed to the presence of

activated macrophages (Cheers and Waller, 1975 ;

Zinkernagel and Blanden, 1975). However, compari-

son of Candida colonization and clearance in germ-

free and mono-associated nude mice and heterozy-


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gous littermates has shown unequivoca lly that the

protective effect is attributable to activation of macro-

phages by a mixed bacter ial flora in the gastrointesti-

nal tract (Lee and Balish, 1982). The responses of

germfree nude mice are indistinguishable from those

of heterozygous controls (Lee and Balish, 1981). An

identica l conclusion - that T lymphocytes are not

essential for clearance of yeasts from infected tissues

-

was drawn from studies of systemic candid&is in

adul t thymectomized, irradiated, bone-marmw-recon-

stituted (ATXBM) mice (Giger et al., 1978).

Nevertheless, a minor role for T cells has not been

definitively excluded, as the limgal burden in the kid-

ney of nude mice was reported to increase late in the

course of infection (Miyake et aZ., 1977). and another

study concluded that the increased susceptibility of

conventional nude mice reconstituted with functional

thymus glands could be interpreted as evidence for an

imunopathological influence of the T-cell compart-

ment (Rogers et al, 1976).

Effect of T-cell-depletion

There are many factors other than macrophage

activation that may confuse interpretation of studies

in mutant mice, including protective and immuno-

pathologica l activities expressed by different T-cell

subsets. An alterna tive approach has been to evalu-

ate the contribution of the differen t T-ce ll subsets to

the development of immune responses and protec-

tion against letha l challenge by depletion using spe-

cific monoclonal antibodies.

The experiments of Coker (Coker et al., 1992)

directly addressed the role of T lymphocytes in

response to lethal challenge by depletion of the

CD4+ or CDS+ lymphocyte subsets. Depletion of

both T-cell subsets increased the mean survival time,

but did not alter the proportion of animals that sur-

vived chal lenge. Further analysis suggested that

CD8+ cells had some potentia l for protection, but

this was negated by a dominant. imtnunopatholog i-

cal response by the CD4+ subset. Recent studies

(Ashman, unpublished) on the effect of T-lympho-

cyte deple tion on the course and severity of sublethal

infection in mice that develop either mild or severe

tissue damage have again failed to demonstrate any

involvement of cell-mediated immunity in recovery

from primary infection. These results reinforce the

established concept that innate immunity plays the

central role in host defence against systemic infec-

tion with C. albicans.

In a different model, depletion of CD4 cells

from mice infected with an attenuated vaccine

strain of C. albicuns increased the fungal burden in

the kidneys (Cenci et al., 1989). but did not alter sur-

vival of primed mice that were cha llenged with a vir-

ulent strain. In further studies, ablation of CD4+ cells

modified the course of a healing infection with the

vaccine strain, and prevented the development of

resistance to reinfection (Romani et al., 1992b).

Concomitant administration of an antiserum specific

for IFNy led to overgrowth of the yeast and the

development of a fata l disease. The resistance to re-

challenge with a virulen t yeast, that was induced by

persistent colon ization with the vaccine strain (Vec-

chiarelli er al., 1988), was abolished by depletion of

either CD4+ or CD8+ cells (Cenci et al., 1990), or by

treatment of the primed mice with a polyclonal anti-

serum to IFNY.

The emphasis in these latter experiments was on

the development of protection, and in this context, it

can be noted that T-cell involvement in clearance of

the primary infection, and in the generation of protec-

tive antibodies and memory cell-mediated immune

responses, are distinct phenomena that are not neces-

sarily linked. This means that detection of cell-medi-

ated immune responses (such as DTH) late in the

course of infection does not invar iably signify a

direct chain of causation resulting from T-cell-medi-

ated clearance of primary infection with the organ-

ism. For example, T helper cells are involved in the

process of antibody production to T-dependent anti-

gens, and sublethal in fection with C. albicans results

in the production of protective antibodies whose

effects are more readily demonstrable in mice that

develop severe lesions than in those with mild tissue

damage (Ashrnan and Papadimitriou, 1993). In this

particular case, however, there is no evidence that

T cells are essential for clearance of the primary

infection (Ashman, unpublished); and both primary

and secondary cell-mediated immune responses are

much weaker in the mice with severe lesions (Ash-

man, 1990).

The discrepancies between models in which

clearance of infection is independent of T-lympho-

cyte involvement, and those that demonstrate

T helper effects, have not yet been explained. It is

proposed below that certain aspects may be related

to variations in mechanisms of host defence specific

to different anatomical regions.

The kidney and host responses

Mechanisms of infection

The kidney is a major target organ for infection

with C. albicans, but the pathogenesis of infec tion in

this site is complex, and influenced by a number of

different factors. The crucial issue in terms of host

resistance is the ways in which different effector

pathways can be modulated and/or influenced by the

products of the various resistance genes.

Studies of systemic infection in inbred strains of

mice (Hector et al., 1982 ; Morell i and Rosenberg,


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IMMUNITY TO FUNGI

285

1971) identified the fifth component of complement

(C5) as a major influence on susceptibility and resis-

tance, in that CS-deficient animals were acutely sus-

ceptible to lethal challenge. However, not all C5-

deficient mice are equally susceptible to infection,

and there are substantial differences in the magni-

tude of the fungal burden and extent of tissue

destruction between organs and tissues in particular

anatomical regions. Histological and quantitative

comparisons of infection in three CS-deficient

strains of mice showed that the kidney was the organ

most severely affected by infection with C. albicuns

in CS-deficient, as compared with CS-sufficient,

mouse strains (Ashman et al., 1996). However, sig-

nificant differences were observed between mouse

strains, in that CS-deficient AKR mice showed sig-

nificantly lower levels of kidney colonization and

reduced mortality when compared with A/J or

DBA/2. These findings led to the identification of

the Curg2 gene described above, but also focussed

attention on the patterns of infection and host

Carg2 ,Hc

Carg2 ,Hc

responsiveness in this organ, as opposed to other

anatomical regions, and on the relationship between

fungal colonization and mortality.

There is a direct relationship between colony

counts in the infected kidney and mortality (Mar-

quis et al., 1988 ; Salvin and Neta, 1983); in as

much as the immediate cause of death after acute

systemic challenge is acute fungal pyelonephritis.

Infection in other sites, such as the brain, is unre-

lated to mortality (Ashman et al., 1993), and organ-

specific diseasecan best be understood with refer-

ence to the genetic makeup of the mouse (fig. 1).

However, this is not a complete explanation, as the

kidney exhibits an unusually protracted pattern of

infection, with viable yeasts being recovered for

periods in excess of 56 days (Louria, 1985). The

reason for this susceptibility is unknown, although it

has been postulated that it is the unique architecture

of the kidney (Louria et al., 1963), rather than more

subtle variables, that allows the yeast to evade the

host defences.

Carg2 ,Hc

Time after infection

+ Mortality

Threshold

Fig. 1. A schematic epresentationof the effects of C. albicans resistancegene2 (Carg2) and

haemolytic complement

Hc)

on fungal colonization n

the kidney of

inbred mice.

The Cargl allele is assumed to be the same in each example. It will be noted in the right hand

panel that even when the fungal burden exceeds the threshold for mortal ity, colonization of the brain

remains low. In CS-suffic ient mice, the Carg2 allele has only a minor effect on the number of fun-

gal colonies in the kidneys.


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Phugocytosis and host resistance

Polymorphonuclear leucocytes make the major

contribution to the defence of the kidney (Fulurija et

aZ., 1996), but activation of macrophages/monocytes

also plays an important part. This latter was demon-

strated by enhancement of the innate resistance of

the kidney against C. albicans by treatment of the

animals with muramyl dipeptide (Marquis et al.,

1992). The relevance of this experiment to the

present discussion is that treatment resulted in signif-

icant reduction in fungal counts in the kidney of

susceptible DBAZ2, but not resistant C57BL/6

mice. As noted above (table I), DBA/2 mice are pro-

posed to be Hc0,Carg2S, whereas C57BL/6 are

Hc,Carg2, which suggests that there may be a

genet ic component in the responsiveness uf kidney

phagocytes to activation.

A similar augmentat ion of anti-Candida resis-

tance is induced by infection with a vaccine strain

of the yeast, which establishes a long-lasting

chronic infection without causing death (Vecchia-

rel li et aZ., 1988). The protective activity was non-

specific, could be reproduced in athymic mice (Bis-

tom et al., 1988), and showed a strong correlat ion

with macrophage activa tion (Bistoni et al., 1986;

Vecchiarelli et al., 1988). The strain specificity of

this effect (if any) has not been reported. Activation

of macrophages in this model was associated with

high serum levels of GM-CSF, TNFa, IL1 and

IFNy. These cytokines were also detected in the

supematants of spleen cell cultures (Vecchiarel li et

aZ., 1989), and cytokine production was found to

correlate with the expression of microbicidal activ-

ity in vivo. As described above, this model was then

used to demonstrate reciprocal regulation of resis-

tance and susceptibility by Th, and Th, cytokines,

respectively.

Is there a way to reconcile the T-dependent and

T-independent models of infection, and are T helper

cytokines crucial to the expression of susceptibility

and resistance? One hypothesis that could resolve

some of the anomalies is that recovery from sub-

lethal infection occurs essentially independently of

T cells and Th cytokines - a proposition that is

consistent wrt the results of infection in IFNy

knockout mice (Qian and Cutler, 1997) - whereas

more severe challenges result in the genera tion of

Th -type cytokines that may be either associated

l

or contribute to, progressive disease.

The development and kinetics of systemic candi-

diasis in mice are heavily influenced not only by

the inbred strain in which infec tion is established,

but also by the magnitude of the challenge (Ash-

man et al., 1996). DBA/2 mice, which are widely

regarded as a high ly susceptible strain, have a

genetic endowment that renders them unusually

susceptible to kidney colonization, but they are

capable of effic ient clearance of lower infectious

doses (Ashman et uZ., 1993, 1996). The resistance

of the kidney can be enhanced by treatments that

lead to macrophage activation (Marquis et al.,

1992) ; however, the candidacidal activity of mac-

rophages activated by IFNy in vitro is strongly

inhibited by IL4 or ILlO, either separately or in

combination (Cenci et al., 1993).

Production of Th, cytokines in vivo is strictly

dose-dependent (Mencacci et al., 1996), and neu-

tralization of either cytokine in mice with non-heal-

ing infections was shown to reduce the fungal bur-

den and increase survival (Romani et al., 1992~;

Romani et uZ., 1994). The morta lity associated with

exper imenta l systemic candidiasis is generally

attributable to acute fungal pyelonephritis, so

decreasing the fungal burden in the kidney by atten-

uation or reversal of Th, cytokine-mediated de-acti-

vation of macrophages would avert early death from

overwhelming loca l infection. However, this pro-

cess would not necessarily affect the ftmgal burden

in other organs, in which responses are governed by

different combinations of effector cells (Fulurija et

al., 1996).

Since Th, cytokine production is associated with

progressive disease, it is necessary to ask whether

the T cells are driving the infection (in an immuno-

pathological sense), or whether cytokine production

by other effector cells may feed back into the T-ce ll

compartment and promote further differentiation

and expansion of the Th, subset. A lthough T helper

cytokines are by def init ion a product of T cells,

there has been increasing interest in, and evidence

for, cytokine product ion by cells outside the T-lym-

phocyte lineage. Natural killer (NK) cell production

of IFNy is well accepted (Bancroft et al., 1991), and

neutrophil secretion of IL10 and IL12 in response to

challenge with C. albicuns has recently been docu-

mented (Romani et al., 1997, 1996).

There is no evidence that NK cells play an

important role in host resistance against systemic

infection (Ashman and Papadimitriou, 1991 ;

Romani et al., 1993); however, acute infec tion

could cause either qualitative or quantitative

changes in the production of inflammatory and pro-

inflammatory cytokines by neutrophils and/or mac-

rophages in the kidney. These changes in the loca l

microenvironment might then have the potentia l to

modulate the T helper profile. The corollary is that

Th

i

responses in chronic disease would be essen-

tial y a bystander phenomenon, driven by deteriorat-

ing innate immunity to the progressive infection.

The arguments developed above allow for the

formulation of testable predictions about the role of

T-cell-derived cytokines in recovery from systemic

candidiasis, and it can be anticipated that an appreci-


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MMUNITY TO FUNGI

287

ation of tbe complex patbogenesis of infection

will

promote a better understanding of the relative roles

of tbe innate and adaptive immune systems, and the

relationship between them.

Acknowledgements

RBA has been supported by a grant from the Arnold Yeldham

and Mary Raine Medical Research Foundation. The research is

currently funded by the National Health

and

Medical Research

Council

of Australia.

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Candida Albicans: Pathogenesis, Immunity and Host Defence