Upload
muhammadyogawardhana
View
224
Download
0
Embed Size (px)
Citation preview
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
1/8
IMMUNITY TO FUNGI
281
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.
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
2/8
282
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
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
3/8
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-
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
4/8
73rd FORUM IN IMMUNOLOGY
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,
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
5/8
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.
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
6/8
73rd FORUM IN IMMUNOLOGY
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-
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
7/8
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.
References
Ashman, R.B. (1990), Murine candidiasis : cell-mediated
immune responses correlate directly with susceptibil-
ity and resistance to infection. Immunol. Cell Biol.,
68, 15-20.
Ashman, R.B., Bolitho, E.M. Fulurija , A. (1993, Cyto-
kine mRNA in brain tissue f rom mice that show
strain-dependent differences in the severity o f lesions
induced by systemic infection with Candida albicans
yeast . J. Infec t. Dis., 172, 823-830.
Ashman, R.B., Bolitho, E.M. & Papadimitriou, J.M. (1993),
Patterns of resistance to Candida albicans in inbred
mouse strains. Immunol. Cell Biol., 71, 221-225.
Ashman, R.B., Fulurija, A. & Papadimitriou, J.M. (1996),
Strain-dependent differences in host response to Can-
dida albicans infect ion in mice are related to organ
susceptibility and infectious load. Infec t. Immun., 64,
1866-1869.
Ashman, R.B., Fulurija, A. & Papadimitriou, J.M. (1997),
Evidence that two independent host genes influence
the sever ity of tissue damage and susceptibility to
acute pyelonephritis in murine sys temic candidiasis.
Microb. Pathog., 22, 187-192.
Ashman, R.B. & Papadimitriou, J.M. (1987), Murine can-
didiasis. Pathogenesis and host responses in geneti-
cally distinc t inbred mice. Immunol. Cell Biol., 65,
163-171.
Ashman, R.B. & Papadimitriou, J.M. (1989). Genetic reg-
ulation of pathogenesis and host responses in fungal
infection, in Immunology of Fungal Infection (E.
Kurstak & G. Marquis) (pp. 347-371). Marcel Dek-
ker, New York.
Ashman, R.B. & Papadimitriou, J.M. (1991), Susceptibil-
ity of beige mutant mice to candidiasis may be linked
to a defec t in granulocyte production by bone marrow
stem cells. Infec t. Immun., 59, 2140-2146.
Ashman, R.B. & Papadimitriou, J.M. (1992), Genetic
resistance to Candida albicans infect ion is conferred
by cells derived from the bone marrow. J. Infec t.
Dis., 166, 947-948.
Ashman, R.B. & Papadimitriou, J.M. (1993), Strain depen-
dence of antibody-mediated protection in murine
systemic candidiasis. J. Infec t. Dis., 168, 511-513.
Ashman, R.B. & Papadimitriou, J.M. (1995), Production
and funct ion of cytokines in natural and acquired
immunity to Candida albicans infection. Microbial.
Rev., 59, 646672.
Bancroft, G.J., Schreiber, R.D. & Unanue, E.R. (1991),
Natural immunity: a T-cell-independent pathway of
macrophage activation, defined in the scid mouse.
Immunol. Rev ., 124, 5-24.
Bistoni, F., Vecchiarelli, A., Cenci, E., Puccetti, P., Mar-
coni, P. & Cassone, A. (1986), Evidence for macro-
phage-mediated protection against lethal Candida
albicans infection. Infec t. Immun., 51, 668-674.
Bistoni, F., Verducci, G., Perito, S., Vecchiarelli, A., Puc-
cett i, P., Marconi, P. & Cassone, A. (1988), Immuno-
modulation by a low-virulence, agerminative variant
of Candida albicans. Further evidence for macro-
phage activation as one of the effec tor mechanisms of
nonspecific anti-infectious protection. J. Med. Vet.
Mycol., 26, 285-299.
Blasi, E., Puliti, M., Pitzurra, L., Bartoli, A. & Bistoni, F.
(1994), Heterogeneous secretory response of phagoc-
ytes from different anatomical districts to the dimor-
phic fungus Candida albicans. Cell. Immunol. , 153,
239-247.
Cenci, E., Romani, L., Mencacci, A., Spaccapelo, R., Schi-
affella , E., Puccetti, P. & Bistoni, F. (1993). Interleu-
kin-4 and interleukin-10 inhibit n itric oxide-depen-
dent macrophage killing of Candida albicans. Eur. J.
Immunol., 23, 1034-1038.
Cenci, E., Romani, L., Vecchiarelli, A., Puccetti, P. &
Bistoni, F. (1989), Role of L3T4+ lymphocytes in
protective immunity to systemic Candida albicans
infection in mice. Infect. Immun., 57, 3581-3587.
Cenci, E., Romani, L., Vecchiarelli, A., Puccetti, P. &
Bistoni, F. (1990), T cell subsets and IFN-gamma
production in resistance to sys temic candidosis in
immunized mice. J. Immunol., 144,4333-4339.
Cheers, C. & Waller, R. (1975), Activated macrophages in
congenitally athymic nude mice and in lethally
irradiated mice. J. Immunol. , 115, 844-847.
Coker, L.A., Mercadal, C.M., Rouse, B.T. & Moore, R.N.
(1992), Differential effe cts of CD4+ and CDS+ cells
in acute, systemic murine candidosis. J. Leukoc.
Biol., 51, 305-306.
Cutler, J.E. (1976), Acute systemic candid&is in normal
and congenitally thymic-deficient (nude) mice.
J. Reticuloendothel. Sot., 19, 121-124.
Decker, T., Lohmann-Matthes, M.L. & Baccarini, M.
(1986), Heterogeneous act iv ity of immature and
mature cells of the murine monocyte-macrophage lin-
eage derived from different anatomical districts
against yeast-phase Candida albicans. Infec t.
Immun., 54,477-486.
Fulurija, A., Ashman, R.B. & Papadimitriou, J.M. (1996),
Neutrophil depletion increases susceptibil ity to
systemic and vaginal candid&is in mice, and reveals
differences between brain and kidney in mechanisms
of host resistance. Microbiology, 142, 3487-3496.
Fulurija, A., Ashman, R.B. & Papadimitriou, J.M. (1997),
Increased tissue resistance in the nude mouse against
Candida albicans without altering strain-dependent
differences in susceptibility. J. Med. Vet. Mycol., 35,
197-203.
Giger, D.K., Domer, J .E., Moser, S.A. & McQuitty, J.T.,
Jr. (1978), Experimental murine candidiasis : patho-
logical and immune responses in T-lymphocyte-
depleted mice. Infec t. Immun., 21, 729-737.
Hector, R.F. , Domer, J.E. & Carrow, E.W. (1982),
Immune responses to Candida albicans in genetically
distinct mice. Infect. Immun., 38, 1020-1028.
Lee, K.W. & Balish, E. (1981). Systemic candidosis in
7/25/2019 Candida Albicans: Pathogenesis, Immunity and Host Defence
8/8
288
73rd FORUM IN IMMUNOLOGY
germfree, flora-defined and conventional nude and
thymus-bearing mice. J. Reticuloendothel. Sac., 29,
71-77.
Lee, K.W. & Balish, E. (1982), Eff ect o f T-cells and intes-
tinal bacteria on resistance of mice to candidosis.
J. Reticuloendothel. Sot., 31, 233-240.
Louria, D.B. (1985), Candida infec tions in experimental
animals, in Candidiasis (G.P. Bodey & V. Fain-
stein) (pp. 29-51). Raven Press, New York.
Louria, D.B., Brayton, R.G. & Finkel, G. (1963), Studies
on the pathogenesis of experimental Cundidu albi-
cans infect ions in mice. Sabouraudia, 2, 271-283.
Mahanty, S., Greenfield, R.A., Joy ce, W.A. & Kincade,
P.W. (1988), Inoculation candidiasis in a murine
model of severe combined immunodeficiency syn-
drome. Infect. Immun., 56, 3162-3166.
Marquis, G., Montplaisir, S., Pelletier, M., Auger, P. &
Lapp, W.S. (1988), Genetics of resistance to infec-
tion with Candida albicans in mice. Br. J. Exp.
Pathol., 69, 65 l-660.
Marquis, G.A., Boushira, M., Russo, P. & Montplaisir, S.
(1992), Influence of mummy1 dipeptide on renal can-
didiasis in genetically distinc t mice. APMIS, 100,
967-975.
Mencacci, A., Cenci, E., Spaccapelo, R., Tonnetti, L. &
Romani, L. (1995), Rationale for cytokine and anti-
cytokine therapy of Candida albicans infection.
J. Mycol . Med., 5, 25-30.
Mencacci, A., Spaccapelo, R., Delsero, G., Enssle, K.H.,
Cassone, A., Bistoni, F. & Romani, L. (1996), CD4+
T-helper-cell responses in mice with low-level Can-
dida albicans infection. Infec t. Immun., 64, 4907-
4914.
Miyake, T., Takeya, K., Nomoto, K. & Muraoka, S.
(1977), Cellular elements in the resistance to Can-
dida infection in mice. I. Contribution of T lympho-
cytes and phagocytes at various stages of infection.
Microbial. Immunol. , 21, 703-725.
Morelli, R. & Rosenberg, L.T. (1971), Role of comple-
ment during experimental Candida infection in mice.
Infec t. Immun., 3, 521-523.
Papadimitriou, J.M. & Ashman, R.B. (1986), The patho-
genesis of acute systemic candid&is in a susceptible
inbred mouse strain. J. Pathol., 150, 257-265.
Puccetti, P., Mencacci, A., Cenci, E., Spaccapelo, R.,
Mosci, P., Enssle, K.H., Romani, L. & Bistoni, F.
(1994), Cure of murine candidiasis by recombinant
soluble interleukin-4 receptor. J. Infect . Dis., 169,
1325-1331.
Qian, Q.F. & Cutler, J .E. (1997), Gamma interferon is not
essential in host defense against disseminated candi-
diasis in mice. Infect . Immun., 65, 1748-1753.
Rogers, T.J. , Balish, E. & Manning, D.D. (1976), The role
of thymus-dependent cell-mediated immunity in
resistance to experimental disseminated candidiasis.
J. Reticuloendothel. Sot., 20, 291-298.
Romani, L., Cenci, E., Mencacci, A., Spaccapelo, R.,
Grohmann, U., Puccetti, P. & Bistoni, F. (1992a),
Gamma interferon modifies CD4+ subset expression
in murine candidiasis. Infect . Immun., 60,4950-4952.
Romani, L., Mencacci, A., Cenci, E., Delsero, G., Bistoni,
F. & Puccetti, P. (1997), An immunoregulatory role
for neutrophils in CD4+ T helper subset selection in
mice with candidiasis. J. Immunol. , 158, 2356-2362.
Romani, L., Mencacci, A., Cenci, E., Mosci, P., Vitellozzi,
G., Grohmann, U., Puccett i, P. 8z Bistoni, F. (1992b),
Course of primary candidiasis in T cell-depleted mice
infected with attenuated variant cells. J. Infec t. Dis.,
166, 1384-1392.
Romani, L., Mencacci, A., Cenci, E., Puccetti, P. &
Bistoni, F. (1996), Neutrophils and the adaptive
immune response to Candida albicans. Res. Immu-
nol., 147, 512-518.
Romani, L., Mencacci, A., Cenci, E., Spaccapelo, R., Schi-
affella , E., Tonnetti, L., Puccetti, P. & Bistoni, F.
(1993), Natural killer cells do not play a dominant
role in CD4+ subset differentiation in Candida albi-
cans-infected mice. Infec t. Immun., 61, 3769-3774.
Romani, L., Mencacci, A., Grohmann, U., Mocci, S.,
Mosci, P., Puccetti, P. & Bistoni, F. (1992~). Neutral-
izing antibody to interleukin 4 induces systemic pro-
tection and T helper type l-associated immunity in
murine candidiasis. J. Exp. Med., 176, 19-25.
Romani, L., Puccetti, P., Mencacci, A., Cenci, E., Spacca-
pelo, R., Tonnetti, L., Grohmann, U. & Bistoni, F.
(1994), Neutralization of IL-10 up-regulates nitric
oxide production and protects susceptible mice from
challenge with Candida albicans. J. Immunol., 152,
3514-3521.
Salvin, S.B. & Neta, R. (1983), Resistance and suscepti-
bili ty to infect ion in inbred murine strains. I. Varia-
tions in the response to thymic hormones in mice
infected with Candida albicans. Ceil. Immunol., 75,
160-172.
Vecchiarelli, A., Cenci, E., Puliti, M., Blasi, E., Puccetti,
P., Cassone, A. & Bistoni, F. (1989), Protective
immunity induced by low-virulence Candida albi-
cans: cytokine production in the development of the
anti-infectious state. Cell. Immunol. , 124, 334-344.
Vecchiarelli, A., Mazzolla, R., Farinelli, S., Cassone, A. &
Bistoni, F. (1988), Immunomodulation by Candida
albicans: crucial role of organ colonization and
chronic infect ion with an attenuated agerminative
strain of C. albicans for establishment of anti-infec-
tious protection. J. Gen. Microbial., 134, 2583-2592.
Zinkemagel, R.M. & Blanden, R.V. (1975), Macrophage
activation in mice lacking thymus-derived (T) cells.
Experientia, 31,591-593.