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REVIEW
Opportunistic yeast pathogens: reservoirs, virulence mechanisms,
and therapeutic strategies
Elizabeth J. Polvi •Xinliu Li •Teresa R. O’Meara •
Michelle D. Leach •Leah E. Cowen
Received: 24 December 2014 / Revised: 6 February 2015 / Accepted: 11 February 2015
ÓSpringer Basel 2015
Abstract Life-threatening invasive fungal infections are
becoming increasingly common, at least in part due to the
prevalence of medical interventions resulting in immuno-
suppression. Opportunistic fungal pathogens of humans
exploit hosts that are immunocompromised, whether by
immunosuppression or genetic predisposition, with infec-
tions originating from either commensal or environmental
sources. Fungal pathogens are armed with an arsenal of
traits that promote pathogenesis, including the ability to
survive host physiological conditions and to switch be-
tween different morphological states. Despite the profound
impact of fungal pathogens on human health worldwide,
diagnostic strategies remain crude and treatment options
are limited, with resistance to antifungal drugs on the rise.
This review will focus on the global burden of fungal in-
fections, the reservoirs of these pathogens, the traits of
opportunistic yeast that lead to pathogenesis, host genetic
susceptibilities, and the challenges that must be overcome
to combat antifungal drug resistance and improve clinical
outcome.
Keywords Opportunistic Fungi Yeast Pathogen
Candida Cryptococcus Histoplasma Pneumocystis
Abbreviations
ABPA Allergic bronchopulmonary aspergillosis
APECED Autoimmune polyendocrinopathy–
candidiasis–ectodermal dystrophy
cAMP Cyclic AMP
CDC Centers for Disease Control and Prevention
CGD Chronic granulomatous disease
CLR C-type lectin receptors
CMC Chronic mucocutaneous candidiasis
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
CRP C-reactive protein
ECM Extracellular matrix
GUT Gastrointestinally induced transition
GXM Glucuronoxylomannan
GXMGal Glucuronoxylomannogalactan
HAART Highly active antiretroviral therapies
HIES Hyper-IgE syndrome
HSP Heat shock protein
IFN-cInterferon-c
IL Interleukin
IRIS Immune reconstitution inflammatory
syndrome
MPO Myeloperoxidase
MR Mannose receptors
NF-jB Nuclear factor-jB
NO Nitric oxide
PAMP Pathogen-associated molecular pattern
PCP Pneumocystis pneumonia
PKA Protein kinase A
PKC Protein kinase C
PRR Pattern recognition receptors
SAP Secreted aspartyl proteinase
TGF-bTransforming growth factor-b
E. J. Polvi and X. Li contributed equally to this work.
E. J. Polvi X. Li T. R. O’Meara M. D. Leach
L. E. Cowen (&)
Department of Molecular Genetics, University of Toronto,
1 King’s College Circle, Medical Sciences Building, Room
4368, Toronto, ON M5S 1A8, Canada
e-mail: leah.cowen@utoronto.ca
M. D. Leach
Aberdeen Fungal Group, Institute of Medical Sciences, School
of Medical Sciences, University of Aberdeen, Foresterhill,
Aberdeen, UK
Cell. Mol. Life Sci.
DOI 10.1007/s00018-015-1860-z Cellular and Molecular Life Sciences
123
TLR Toll-like receptors
TNF-aTumor necrosis factor-a
Treg cell Regulatory T cell
VVC Vulvovaginal candidiasis
Introduction
The emergence of fungi occurred approximately 1.6 billion
years ago [1,2]. With an estimated 1.5 million species
occupying a range of environments [3], fungal species are
extraordinarily diverse. Fungi are a major cause of disease
in insects, amphibians, plants and even other fungi, with
incidences of infection reaching unprecedented levels in
recent years. Strikingly, millions of acres of the world’s
forests have become victim to fungal infections. The blue
stain fungus Grosmannia clavigera has devastated North
American pine forests [4], and elm trees have been in
significant decline since the twentieth century due to Dutch
elm blight. Fungi also pose a major threat to food supplies,
being responsible for the destruction of wheat and barley
crops by wheat leaf rust and rice by rice blast fungus.
Additionally, fungi pose a significant threat to animals,
crippling bat and amphibian species worldwide [5].
Of the 1.5 million fungal species, around 300 are re-
ported to be pathogenic in humans, and only a minority of
these are common human pathogens [6]. Many fungi are
commensal, forming part of our natural microbiota. Indeed,
a recent study by Findley et al. [7] illustrated the diversity
of fungal species on three different foot sites, and there is a
growing appreciation that fungi have an important role in
defining commensal microbial communities [8]. This
commensal role allows fungi to infect humans in multiple
ways. Ranging from cutaneous infections affecting 29
million North Americans each year [9], to superficial skin
infections, to more than 2 million invasive fungal infec-
tions per year worldwide [10], commensal fungi have
important roles in disease, being capable of switching to
opportunistic pathogens. It is the opportunistic nature of
fungal pathogens that triggered a stark rise in fungal in-
fections in the late twentieth century, primarily in hosts
with impaired immunity due to medical interventions such
as chemotherapy for cancer, organ transplantation, or in-
fection with HIV [11]. Overall, fungi are the cause of
billions of infections worldwide, killing over 1.5 million
people annually [10,12]. Species of Aspergillus,Candida,
Cryptococcus and Pneumocystis are at the forefront of
fungal infections, accounting for approximately 90 % of
human mortality cases [10]. Poor diagnostic tools and an-
tifungal drug resistance accounts for a 50 % or higher
mortality rate in patients with systemic fungal infections
[11].
It has been postulated that global warming is in part
responsible for the drastic increase in fungal infections,
leading to the devastating loss of forests and crops
worldwide. Remarkably, the common denominator of all
human pathogenic fungi is the ability to grow at host
temperatures [13,14]. The steady rise in temperature upon
climate change will selectively enable adaptation of fungi,
broadening the array of species able to survive at host
temperature [15]. Indeed, clinical isolates of the generally
benign yeast Saccharomyces cerevisiae that exhibit en-
hanced capacity to grow at higher temperature (41 °C)
compared to laboratory strains, were able to survive in
mice [16]. The common fungal pathogens Cryptococcus
neoformans,Histoplasma capsulatum and Aspergillus fu-
migatus are found in environments as diverse as pigeon
excreta and soil, yet each retains the capacity to grow at
37 °C. Many of the genes required for growth at high
temperatures in these pathogens are necessary for virulence
and some are required for survival [17–19]. Consequently,
high temperature growth is essential for pathogenesis. This
review will focus on the reservoirs and mechanisms of
pathogenic yeast infections, the challenges faced upon in-
fection and the hurdles that must be overcome to combat
antifungal drug resistance.
Global burden of fungal infections
Superficial and mucosal fungal infections are extremely
common, but life-threatening systemic fungal infections
are generally limited to immunocompromised individuals
[20,21]. The population of vulnerable individuals expe-
riencing some form of altered immune function due to the
HIV/AIDS epidemic, hospitalization, chronic illnesses,
antibiotic-mediated microbiota alteration, or che-
motherapies continues to increase [10,22,23], and has led
to billions of cases of invasive fungal infections
worldwide.
Cryptococcus
Cryptococcus neoformans is the leading cause of deaths
due to fungal infections, with a global burden of nearly 1
million cases annually, and more than 620,000 deaths
worldwide [23]. Cryptococcus is ubiquitous and globally
distributed, with more than 70 % of children older than 5
demonstrating serum reactivity against cryptococcal pro-
teins [24]. A major risk factor for cryptococcal infections is
immunosuppression due to HIV/AIDS. In resource-limited
areas with high rates of HIV/AIDS, the mortality rate ap-
proaches 70 % [23], and cryptococcal meningitis is
considered an AIDS-defining illness [25]. Left untreated,
cryptococcal meningitis is uniformly fatal.
E. J. Polvi et al.
123
In Western Europe and North America, the overall
mortality rate of cryptococcal infections is 10 %, with
approximately 700 deaths per year [23]. However, nearly
20 % of cryptococcosis cases in the US are in non-HIV
patients [26], and the mortality rate of these infections can
be greater than 30 % [27]. Many of these infections are in
patients with conditions associated with immunosuppres-
sion or with solid organ transplants, although there are
some incidences of underlying genetic susceptibility to
fungal infections [26–28].
Another source of cryptococcosis in immunocompetent
individuals is infections due to Cryptococcus gattii, which
has caused an outbreak in the Pacific Northwest over the
last 15 years [29–31]. The majority of these cases have
been in immunocompetent individuals, and many cases
were fatal despite antifungal therapies [31]. Although the
origin of the outbreak was Vancouver Island, cases of C.
gattii infections have been documented along the pacific
coast and in Florida [32,33].
An additional complication in cryptococcal treatment is
the occurrence of immune reconstitution inflammatory
syndrome (IRIS), where restoration of immune function
after starting highly active antiretroviral therapies
(HAART) results in enhanced and destructive immune
responses to subclinical or cleared microbial infections
[34]. Recent studies have reported that between 8 and 50 %
of AIDS patients develop cryptococcal IRIS after treatment
with HAART, and the mortality rate ranges between 30 and
60 % [35,36].
Candida
Candida species are normal members of the human mu-
cosal microbiota; studies have estimated between 25 and
40 % of people are colonized with Candida albicans at any
given point [37,38]. However, C. albicans also causes
more than 400,000 deaths per year due to invasive can-
didiasis [39]. Disseminated Candida infections have an
attributable mortality rate approaching 40 %, even with
antifungal therapies [39].
Patients with HIV/AIDS or other forms of impaired
immunity, especially neutropenia, are vulnerable to dis-
seminated candidiasis [25,39,40]. Additionally, Candida
species are the fourth most common cause of hospital-ac-
quired bloodstream infections, and the incidence of
Candida infections is increasing [41]. Candida albicans is
the most common causal agent of nosocomial infection
among the Candida species, followed by C. glabrata,C.
parapsilosis, and C. tropicalis [41]. Many of these infec-
tions may be due to breakdown of mucosal surfaces during
hospitalization or treatment, which then allows the super-
ficial Candida colonization access to the bloodstream [42,
43]. Finally, C. albicans can form biofilms on medically
implanted devices and catheters, creating a reservoir for
bloodstream infections [44,45].
Recently, mortality rates due to C. albicans infections in
high-risk patients, such as stem cell transplant recipients or
those undergoing therapy for leukemia, have decreased due
to prophylactic fluconazole therapies [39,42]. However,
resistance can occur [46,47], and the Centers for Disease
Control and Prevention (CDC) has ranked fluconazole-re-
sistant Candida as a serious threat [48].
Pneumocystis
Pneumocystis is an almost ubiquitous colonizer of human
lungs, with approximately 80 % of children demonstrating
serum antibodies to the organism [49–51]. However, it can
also cause pneumocystis pneumonia (PCP) in immuno-
compromised hosts. In the early years of the AIDS
epidemic, PCP was the most common clinical manifesta-
tion of decreased immune function [52]. Before HAART,
approximately 65 % of AIDS patients in the United States
exhibited PCP [52,53]. Recent studies in developing na-
tions have suggested that up to 40 % of HIV-infected
patients exhibit PCP [52,54]. An extrapolation of the
current epidemiological reports suggests that there are
more than 400,000 cases per year [10,54].
Pneumocystis pneumonia remains one of the leading
causes of morbidity and mortality worldwide [50]. In de-
veloped nations with readily available HAART, the
mortality rate has dropped to approximately 10 % [55,56].
However, in a recent study of pulmonary disease in AIDS
patients in Uganda, the number of cases of PCP was lower
than for tuberculosis or cryptococcal pneumonia, but the
mortality was higher, with 75 % of the patients dying
within 2 months of admission [57]. Additionally, Pneu-
mocystis infections may also contribute to impaired lung
function and increased mortality of patients with chronic
obstructive pulmonary disease (COPD) [50,58].
Aspergillus
Aspergillus is a ubiquitous filamentous fungus, and people
are faced with continuous exposure to Aspergillus spores.
As an opportunistic pathogen, Aspergillus mainly causes
disease in patients with impaired immune function. Most
infections are acquired exogenously instead of through
reactivation of latent infections [59]. The most vulnerable
population includes patients with neutropenia, organ or
bone marrow transplant, or those undergoing immunosup-
pressive therapies [42,59,60]. Invasive aspergillosis is
uniformly fatal if untreated, and even with current treat-
ment options, mortality remains at 50 % [42,61]. Current
reports suggest that there are more than 200,000 cases of
invasive aspergillosis per year [10].
Opportunistic yeast pathogens
123
Aspergillus can also cause allergic bronchopulmonary
aspergillosis (ABPA), and recent estimates suggest that the
global burden of ABPA is 4,837,000 patients [62,63].
Patients with lung disease, such as COPD, cystic fibrosis,
or emphysema are especially susceptible to ABPA [59,60,
63]. Infection with Aspergillus can increase the mortality of
these underlying diseases, contributing to the 100,000
deaths per year [10].
Histoplasma
Histoplasma capsulatum is endemic to the Midwest United
States and Central America, though it has a global distri-
bution [64]. Histoplasma is the most prevalent cause of
systemic mycosis in Central America, and it infects several
hundred thousand individuals annually [64,65]. Recent
studies estimate nearly 80 % of the adult population in the
endemic areas show previous infections by Histoplasma
[64]. Most of these infections occur in immunocompetent
hosts, but the majority does not display symptoms. How-
ever, individuals who are exposed to large numbers of
spores can suffer from acute pulmonary histoplasmosis.
Additionally, the disease is more severe in patients with
underlying lung disease [64,65]. Disseminated histoplas-
mosis usually only occurs in individuals with compromised
immune systems [64,66]. Mortality due to disseminated
histoplasmosis remains at 30 %, but it can be reduced with
HAART [65].
Paracoccidioides
Paracoccidioides is an endemic dimorphic fungal patho-
gen in South America, and it is the most common cause
of invasive mycosis in this region [65]. Nearly 10 million
people are infected with this organism, but in most cases,
the host immune system can prevent the conidia from
causing disease [65]. However, individuals with compro-
mised immune systems or those with decreased lung
function, such as smokers, are vulnerable to expansion of
the yeast from the lungs into disseminated disease [22,
65]. Interestingly, there is not a strong association of
paracoccidiomycosis with HIV [67]. In some cases (be-
tween 5 and 13 %), patients experience relapse of
paracoccidiomycosis due to reactivation of quiescent yeast
cells [68].
Penicillium
Penicillium marneffei is an endemic fungal pathogen in
Southeast Asia, causing disease primarily in immunocom-
promised patients, although infections in immunocompetent
hosts also occur [69,70]. In a study of AIDS patients in
northern Thailand, it was the third most common cause of
infection, after Mycobacterium tuberculosis and C. neofor-
mans [71]. As an opportunistic pathogen, the prevalence of
P. marneffei infections is increasing with the expansion of
the HIV epidemic in Southeast Asia [72].
Penicillium marneffei infections are more common in
the rainy season and are positively correlated with in-
creased humidity [73,74]. This suggests that disease occurs
from primary infections shortly after exposure to the fun-
gus [73]. These disseminated infections are uniformly fatal
without antifungal treatments, but even with rapid admin-
istration of therapeutics, the mortality rate remains
approximately 20 % [71,74]. In children with immune
deficiencies, the mortality rate is higher, at 55 % [70].
Coccidioides
Coccidiomycosis, also known as valley fever, is endemic to
the Southwestern United States and Central America, and it
causes thousands of hospitalizations and approximately
*400 deaths per year in the United States [75]. Coccid-
iomycosis is caused by Coccidioides immitis and
Coccidioides posadasii, which occupy different geographic
regions [76]. Although most infections are self-limiting
lung infections, Coccidioides can also cause disseminated
disease. Risk factors include compromised immune sys-
tems, but agricultural or construction work, outdoor
activity, African or Asian ethnicity, increased age, or
pregnancy also increase vulnerability to Coccidioides.
Additionally, uncontrolled diabetes increases the risk of
disseminated infections [77]. In patients with impaired T
cell function and disseminated infection, mortality rates
were 50 % [76].
Blastomyces
Blastomycosis is caused by infection with Blastomyces
dermatitidis, a dimorphic fungal pathogen that is endemic
in the Midwestern United States. Most infections are due to
spore inhalation during outdoor activities, and ap-
proximately 30–50 % of infections are asymptomatic [78].
Of the symptomatic infections, most can be treated with
antifungal drugs. However, mortality ranges between 4 and
22 % [78]. In a recent outbreak in Wisconsin, 70 % of the
cases were hospitalized and 5 % died [79]. Only 25 % of
the infected patients had any form of compromised im-
mune system. However, there appears to be genetic risk
factors for blastomycosis as the incidence rate is 12 times
higher for Asians [79].
Rhizopus and Mucor
Mucormycosis is due to infections by basal fungi, most
often by species of Rhizopus and Mucor [80]. Vulnerable
E. J. Polvi et al.
123
populations include patients with hematopoietic stem cell
transplants or other hematological malignancies, those with
diabetes, and those with compromised immune systems
[80,81]. The association between mucormycosis and dia-
betes is particularly strong; a recent study showed that
70 % of mucormycosis patients had diabetic ketoacidosis
[81]. The mortality rate can be as high as 90 % for dis-
seminated infections [82,83]. Cutaneous mucormycosis
can also occur after natural disasters, when environmental
spores are disturbed and patients have open wounds [84].
The case-fatality rate for cutaneous mucormycosis can be
as high as 80 % [84,85].
Sporothrix
Sporotrichosis is usually caused by traumatic inoculation
by material contaminated with Sporothrix schenckii,
although there are some cases of inhalational sporotrichosis
[86]. Although the infections are restricted to the site of
infection, there are cases of disseminated sporotrichosis,
mostly in immunocompromised individuals [67]. A recent
study of cases in HIV-infected patients in Brazil found that
the incidence of sporotrichosis was increasing to the point
where there the incidence was comparable to histoplas-
mosis and cryptococcosis [67]. Of the patients with both
HIV and sporotrichosis, almost 40 % were hospitalized for
disseminated infection [67].
Trichosporon
Like Candida,Trichosporon can exist as a member of the
normal human microbiota [87]. However, patients with
malignant hematological disorders are vulnerable to in-
fection with Trichosporon [87]. Trichosporon infections
are the second most common cause of disseminated fungal
infections in these patients, although the overall rate is low
[88]. The mortality rate of patients with hematological
disorders and Trichosporon remains at 11 %, even with
antifungal therapies [88].
Reservoirs and nature of infection
Here we discuss the reservoirs and nature of infection,
focusing on the predominant opportunistic yeast and yeast-
like pathogens, Cryptococcus,Candida,Histoplasma, and
Pneumocystis.
Cryptococcus
Cryptococcus species are found ubiquitously in nature, but
only C. neoformans and C. gattii are considered serious
human pathogens [89,90]. The source of human infections
are thought to be exclusively environmental, as there is no
evidence of human to human transmission other than
through contaminated medical devices [91]. Furthermore,
concordance in phenotypic and genotypic characterization
between environmental and clinical isolates within the
same geographical region suggests they belong to the same
fungal population [89,92,93].
Environmental isolates of these yeasts have been re-
ported all around the globe, recovered from soil, dust,
avian excreta, trees and other plants, domestic and wild
animals, as well as marine mammals [94]. Cryptococcus
neoformans is most often found in excreta from pigeons
and other birds. In southern Africa, isolates are commonly
found in the decayed hollows of the mopane tree [95].
Cryptococcus gattii is mostly isolated from tropical and
subtropical regions in association with eucalyptus trees, as
well as from soil, trees, and animals in the Pacific North-
west [94,96]. Plant materials have also been shown to
promote fertility and virulence of C. gattii [97].
Cryptococcal infection occurs upon inhalation of air-
borne fungal cells, generally spores or desiccated yeast [98].
Once inside the host lung, the yeast particles will encounter
either alveolar macrophages or dendritic cells and trigger an
immune response [99]. This can lead to clearance of the
infection, or result in a localized asymptomatic latent in-
fection that is contained within a granuloma, where the
yeast is enveloped by immune cells [99,100]. This latency
period could last for years before reactivation of dormant
infection occurs and disease symptoms develop [89,101].
In the case of C. neoformans, reactivation occurs when host
immunity is compromised, such as in patients with HIV/
AIDS [89]. Cryptococcus gattii infections appear to be new
events as they occur in both immunocompromised and
immunocompetent individuals [102].
Active infection in the lung leads to pneumonia-like
illness, with common symptoms including cough, fever,
and dyspnea, among others [103,104]. Fungal cells can
subsequently disseminate from the lung through vascular or
lymphatic systems to cause systemic infections, with the
central nervous system (CNS) being the preferred desti-
nation [91,100]. Cryptococcus can cross the blood–brain
barrier either directly by transcytosis through the en-
dothelial cells or with the aid of host monocytes [105–107].
Infection of the CNS and brain parenchyma is life threat-
ening and results in cryptococcal meningitis and
meningoencephalitis [104,108]. Neurological symptoms
include headaches, visual and hearing impairment, sei-
zures, and mental status change [108,109].
Candida
Although a large number of Candida species have been
documented, only a few are known to cause disease in
Opportunistic yeast pathogens
123
humans [11,110]. Over 90 % of all Candida infections are
caused by five species: C. albicans,Candida glabrata,
Candida parapsilosis,Candida tropicalis, and Candida
krusei. Among these, C. albicans is by far the most
prevalent, responsible for 90–100 % of superficial mucosal
infections and 40–70 % of disseminated infections [11,
110].
Unlike most other pathogenic fungi, Candida species are
a natural commensal of the human microbiome [111], found
rarely in the soil and external environments, suggesting
adaptation to a parasitic lifestyle [112]. The majority of
Candida infections are from endogenous sources, derived
from commensal populations acquired prior to disease de-
velopment [11,113]. Exogenous sources of infection are
also common, especially in healthcare settings where
transmission can occur from healthcare workers, other pa-
tients, and contaminated medical devices [11,114].
Normally, Candida species exist harmlessly on our skin
and mucosal surfaces as part of the commensal microbiota,
colonizing the skin, oral cavity, gastrointestinal tract, and
reproductive tract [111,115]. However, disruption of the
normal microbial flora or compromising the immune sys-
tem may enable this fungus to overgrow, resulting in
symptomatic infections. Due to the long evolutionary his-
tory with the human host, C. albicans is well adapted to
survive and proliferate in the host environment. The switch
from commensalism to pathogenesis involves significant
changes in the fungus, including regulation of key viru-
lence genes that allows it to quickly sense and adjust to
different sites of infection in the body. Candida species
must overcome different stresses, such as changes in tem-
perature, pH, osmolarity, oxygen and nutrient availability
[14,112,115–118].
Inflammations of the genitourinary tract are common
clinical manifestations of Candida infections, which include
vulvovaginal candidiasis (VVC) in women, balanitis and
balanoposthitis in men, and candiduria in both sexes [119].
VVC, commonly referred to as thrush or yeast infection,
typically presents as isolated occurrences of mild to mod-
erate infection in otherwise healthy women, and are
generally easily controlled with a single-dose therapy [110].
Episodes can occur either sporadically or due to predispo-
sition resulting from a number of risk factors, including
antibiotic use, pregnancy, diabetes, and immunosuppression
[21,120,121]. A subgroup of patients will experience severe
or recurrent VVC, in which case more rigorous and long-
term antifungal therapies are required [110]. It is estimated
that the majority of women develop at least one episode of
VVC in their lifetime [122]. Candida balanitis occurs at a
lower frequency than VVC, though the exact incidence is
unclear due to the lack of population studies [119]. The
disease is generally sexually transmitted and has been as-
sociated with diabetes and antibiotic use [123]. Candiduria,
the presence of Candida species in the urinary tract, is
commonly diagnosed in hospitalized patients, especially
those with a urinary catheter [124–126]. Most cases of can-
diduria are asymptomatic or self-limiting, though it can
cause increased vulnerability to bloodstream infections in
high-risk patients, as well as increased mortality rates and
hospital costs [119,127].
Candida infections can also develop in the mouth or
throat, resulting in oropharyngeal candidiasis. Clinical
manifestations are typically characterized by white or red
lesions on the surfaces of the tongue and oropharynx,
which result in pain and burning sensations, alteration in
taste, and tissue damage [128,129]. Infection is generally
associated with immunosuppression, antibiotic use, en-
docrine alterations, and denture use [128,130]. It is
estimated that over 90 % of HIV-infected patients will
develop oropharyngeal candidiasis at some point during the
progression of their illness [131].
Invasive candidiasis occurs when Candida species break
the mucosal barrier, penetrating into deeper tissue and
gaining access to the bloodstream [132]. Dissemination via
the bloodstream allows the fungus to invade almost all
body sites and organs, resulting in lethal systemic disease
[110]. Major risk factors include immunosuppression, in-
vasive medical procedures, and extended stay in the
intensive care unit [11,133,134]. Early clinical symptoms
of invasive candidiasis are non-specific and resemble other
nosocomial infections, which impede accurate diagnosis
and delays treatment, contributing to increased mortality
[132,135,136].
Pneumocystis
Pneumocystis species are ubiquitous in nature, infecting a
wide variety of mammalian hosts [11,137]. While rodents
were originally thought to be a natural reservoir, it is now
known that Pneumocystis is not zoonotic. Current pheno-
typic and genetic evidence indicates that each mammalian
species that contracts the disease has its own species of
Pneumocystis [137–139]. Pneumocystis jirovecii is re-
sponsible for human infections. However, study of the
organism has been hindered by the inability to culture
Pneumocystis in vitro. Much of what we now know about
P. jirovecii is based on direct clinical evidence or ex-
trapolated from related animal models [50,140].
PCR-based strategies have been used to type and track
the spread of P. jirovecii [141,142]. Children and im-
munocompromised individuals are identified as the most
important sources of P. jirovecii infection [142–145].
While some environmental sources have been identified,
transmission is thought to mostly occur through inhalation
of airborne pathogens that spread from human to human
[146,147].
E. J. Polvi et al.
123
Pneumocystis has strong tropism for the lung, where it
exists as an alveolar pathogen without invading the host
[140]. Infections are typically asymptomatic or subclinical
in the healthy host, but can develop into pneumocystic
pneumonia in immunocompromised individuals, especially
those with HIV infections [50]. Common clinical symp-
toms include progressive dyspnea, nonproductive cough,
low-grade fever, and eventual respiratory failure with dis-
ease progression [140].
Histoplasma
Histoplasma capsulatum exists as a mold in soil environ-
ments and is often associated with bird and bat droppings,
which enhance proliferation of the organism by accelerat-
ing sporulation [148]. Once contaminated, soil can yield
the organism for years after the birds are gone [64]. In-
fections occur through inhalation of the aerosolized H.
capsulatum from disturbed soils. Air currents can also
carry the fungal spore for miles, resulting in infections far
away from contaminated sites [148].
Most infections by H. capsulatum are asymptomatic in
healthy individuals [148]. In children who were exposed
for the first time and in individuals who experienced heavy
exposure to the organism, pulmonary histoplasmosis may
develop [64]. Common symptoms include fever, malaise,
cough, and chest pain. Pulmonary infections can be com-
plicated with infection of the mediastinal lymph nodes,
resulting in Granulomatous mediastinitis.
In immunocompromised patients, such as those infected
with HIV, disseminated histoplasmosis may occur [64,
149,150]. Initial clinical presentation often includes fever,
anorexia, and weight loss. Subsequent severe disease
manifestation includes sepsis, as well as failure of respi-
ratory, renal, and multi-organ systems.
Mechanisms of pathogenesis
Pathogenicity is the ability of a microbe to cause damage to
the host [151]. The ability of an opportunistic pathogen to
cause disease requires the expression of virulence factors.
Here, we outline some of the traits that enable pathogenesis
of the major opportunistic yeast pathogens of humans, C.
albicans,C. neoformans, and H. capsulatum.
High temperature growth
Fungi must be capable of surviving in human host condi-
tions. One trait absolutely required for pathogenicity in
humans is the ability to grow at human body temperature,
37 °C[14]. The most prevalent fungal pathogen, C. albi-
cans, is a natural commensal of mammals and is thus
intrinsically competent for growth at 37 °C. Despite this
thermal adaptation, the heat shock response has been re-
tained in C. albicans and influences virulence [152],
presumably reflecting the importance of febrile tem-
peratures during systemic infection [153]. In C. albicans,
the heat shock response is governed by the transcription
factor Hsf1, and the molecular chaperones Hsp70 and
Hsp90 [14]. Mutant C. albicans strains containing inactive
Hsf1 are thermosensitive and display reduced virulence in
a murine model of systemic candidiasis [154]. Further-
more, the membrane dynamics of C. albicans are crucial
for sensing changes in temperature, with depletion of
OLE1, encoding a fatty acid desaturase, impairing activa-
tion of Hsf1 [155]. Temperature is a central cue that
enables the morphogenetic transition of C. albicans from
yeast to filamentous growth through complex cellular cir-
cuitry [156].
Although the saprobe C. neoformans is usually found in
environmental locales, the ability to grow at human
physiological temperatures allows it to cause disease.
Several signaling pathways have been identified as essen-
tial for C. neoformans growth at elevated temperature,
including Ras1 and Cdc42 signaling [157], the unfolded
protein response [158], the histone acetyltransferase Gcn5
[159], the cell wall integrity pathway [160], and calcineurin
signaling [19]. In addition, increased expression of C.
neoformans Hsp90 and other heat-shock proteins is ob-
served upon infection of a murine lung [161], suggesting a
role for Hsp90 in adapting to host conditions. Mutants that
are unable to grow at 37 °C are unable to cause disease in
murine models of cryptococcosis.
Like C. neoformans, the dimorphic fungus H. capsula-
tum can be found in the soil. However, H. capsulatum
forms mycelia in the environment and changes to the yeast
form upon inhalation by a mammalian host. The increase in
temperature to 37 °C is key for this transition, and mem-
brane dynamics may be involved in sensing this cue [162].
For example, addition of saturated fatty acids with a con-
current increase in temperature amplifies the H. capsulatum
heat shock response [163].
Adaptation to pH
Opportunistic fungal pathogens must not only adapt to
variations in temperature, but also pH. In the host, the pH
can range from acidic (in the vaginal and gastrointestinal
tracts and the immune cell phagolysosome) to basic (such
as in the blood or saliva) [164]. Therefore, pH is a powerful
signal for entry into the host bloodstream or other mi-
croenvironments. Additionally, environmental pH can lead
to alterations in nutrient bioavailability.
In C. albicans, alkaline conditions result in cleavage and
activation of the transcription factor Rim101, which leads
Opportunistic yeast pathogens
123
to the upregulation of genes required for growth in alkaline
conditions, including genes involved in iron acquisition
and morphogenesis [165]. Additionally, Rim101 regulates
expression of genes with roles in adhesion and modulating
the fungal cell wall [166]. PHR1 and PHR2 are pH-re-
sponsive genes regulated by Rim101, with PHR2 being
required for virulence at acidic infection sites (such as the
vaginal tract), whereas PHR1 is required at alkaline sites of
infection (such as the bloodstream) [167]. Mutants lacking
Rim101 have reduced virulence in a mouse model of sys-
temic candidiasis [168].
Cryptococcus neoformans also uses the Rim101 tran-
scription factor to adapt to varying environmental cues.
Similar to C. albicans,CnRim101 is required for growth in
neutral/alkaline conditions, and also regulates expression
of genes required for iron and metal homeostasis [169].
However, in C. neoformans, Rim101 is also activated by
the cyclic AMP (cAMP)/protein kinase A (PKA) pathway
[169]. Rim101 is required to modulate many important C.
neoformans virulence traits, such as attachment of the
polysaccharide capsule [169], the morphological change to
titan cells [170], and modulation of the host immune sys-
tem [171,172]. Upon phagocytosis by macrophages, C.
neoformans enters into an acidic phagolysosome; as a
facultative intracellular pathogen, C. neoformans is well
adapted for growth in acidic conditions [173].
Nutrient limitation
Key to survival is growth. Organisms are often nutrient
starved within the host and must adapt to changes in
available host nutrients. One mechanism by which C. al-
bicans can respond to limited glucose is by secreting
ammonia and autoalkalizing its surroundings to induce
filamentation [174]. For C. neoformans, phagocytosis by
macrophages induces a starvation stress response that in-
cludes upregulation of amino acid and sugar transporters,
gluconeogenesis and fatty acid metabolism [175].
As iron levels are tightly controlled within the host,
microbes must have mechanisms to acquire this essential
cofactor [176]. Although C. albicans and C. neoformans do
not appear to produce their own siderophores, which are
high-affinity iron-binding proteins, they are capable of
transporting xenosiderophores produced by other organ-
isms [177,178]. Additionally, both C. neoformans and C.
albicans are able to use iron from hemoglobin and ferritin
as iron sources [179,180]. Cryptococcus neoformans uti-
lizes a ferric reductase system involving the iron permease
Cft1 and ferroxidase Cfo1 to acquire iron from host
transferrin [181,182]. Mutants lacking these enzymes
show a reduced virulence in a mouse model of crypto-
coccosis. Iron levels are sensed by a master transcription
factor, Cir1, which directs the expression of genes for iron
acquisition. Cir1 is also involved in regulating growth at
physiological temperature, capsule formation, and melanin
production [183], highlighting the central role of iron
regulation in C. neoformans virulence.
Candida albicans is able to acquire iron from he-
moglobin by first binding hemoglobin to a receptor on the
cell wall and subsequently endocytosing this complex
[184]. The heme oxygenase Hmx1 then releases ferrous
iron [185], carbon monoxide, and biliverdin [186]. As
carbon monoxide has immunosupressive properties [187],
its production by Hmx1 may decrease the ability of the host
immune system to clear a C. albicans infection. The hmx1
mutant is unable to cause disease as this mutant is unable to
grow in iron-limited conditions and has a defect in carbon
monoxide production [186,188]. Additionally, the tran-
scriptional activator Sef1 induces iron-uptake genes and
enables virulence, whereas the transcriptional repressor
Sfu1 diminishes expression of iron-uptake genes and en-
ables gastrointestinal commensalism [116]. These genetic
programs may be fundamental to enabling C. albicans to
survive iron depletion in the bloodstream while minimizing
iron toxicity in the gut.
Histoplasma capsulatum is able to both produce side-
rophores and utilize reductive iron assimilation to obtain
the iron necessary for growth [189]. Histoplasma capsu-
latum produces hydroxyamate-type siderophores, and these
siderophores are required for proliferation within macro-
phages and infection in mice [189,190]. Production of
siderophores is negatively regulated by the GATA-type
transcription factor SRE1 [191]. Histoplasma capsulatum
can also take up ferrioxamine B, a xenosiderophore, via
ferric reductases [192].
Changes in cellular shape and size
Host physiological temperature induces a filament-to-yeast
transition in dimorphic fungi, such as H. capsulatum
(Fig. 1). This switch from mycelia to yeast growth at host
temperatures is a requirement for H. capsulatum virulence,
and the histidine kinase Drk1 is a key regulator of this
transition [193]. DRK1-silenced strains show a drastic re-
duction in virulence in a mouse model of histoplasmosis
[193]. In addition, Drk1 regulates expression of two im-
portant H. capsulatum virulence genes, CBP1 and AGS1
[193]. The DNA-binding protein Ryp1 is also essential for
yeast growth, and is related to the C. albicans master
transcriptional regulator of phenotypic switching, Wor1.
Ryp1 is a master regulator of morphogenesis, as it is re-
quired for the expression of yeast-phase-specific virulence
genes and repression of mycelial-specific genes [194].
Recently, a temperature-responsive regulatory circuit
composed of four Ryp proteins was identified that controls
both the transition from filamentous to yeast forms and the
E. J. Polvi et al.
123
expression of virulence genes such as YPS3 and CBP1
[195].
Strikingly, host physiological temperature induces the
opposite morphological transition in the commensal fun-
gus, C. albicans, from yeast to filament compared to the
filament-to-yeast transition initiated in dimorphic fungi
(Fig. 1). Candida albicans is able to undergo various
morphological transitions that facilitate its ability to colo-
nize and infect different niches within the human host. The
most striking of these morphological transitions is that
from yeast to filamentous forms. Typically, chains or
branches of elongated connected cells are referred to as
pseudohyphae [196], whereas cells containing defined
septa between cells and no constrictions in their cell walls
are known as hyphae [197]. Various different environ-
mental cues induce the morphological transition from yeast
to filaments. Many of these cues require a concurrent in-
crease in temperature to 37 °C, and many of the cues
mimic host physiological conditions. For example, serum
is a potent inducer of filamentation at 37 °C, with key
effectors being bacterial peptidoglycans and glucose [198–
200]. At host physiological temperature, deprivation of
nutrients such as carbon or nitrogen can induce a
filamentous program, as can alkaline conditions (pH [6.5)
or elevated CO
2
[201]. The requirement of 37 °C for
filamentation to occur in many cues is due at least in part to
the Hsp90-mediated repression of filamentation, which is
relieved at elevated temperature due to global problems in
protein folding that can overwhelm the functional capacity
of Hsp90 [202]. Many cues induce filamentation in C. al-
bicans via the cAMP–PKA signaling pathway, which
activates transcription factors such as Efg1 [203] and Flo8
[204]. Filamentation is also governed by repressors such as
Nrg1, whose downregulation and degradation is required
for both hyphal initiation and maintenance [205].
The ability of C. albicans to transition between yeast
and filamentous states is key for its dissemination and
virulence in different niches within the host. Invasion of
epithelial cells by C. albicans can occur by either endo-
cytosis or by active penetration by hyphal cells [206]. Cells
locked in the yeast form are reduced in virulence [207,
208], and defective in adhering to and invading oral ep-
ithelial cells [209]. Similarly, cells unable to revert to the
yeast form also have attenuated virulence and show a de-
crease in kidney fungal burden in a murine model of
systemic candidiasis [210]. It is thought that yeast cells are
Fig. 1 Yeast virulence traits. Top,C. albicans can exist as yeast,
filaments, or as a biofilm. Wild-type yeast cells were grown in rich
medium at 30 °C for 24 h. Filaments were grown in RPMI at 37 °C
for 24 h. The biofilm is fluconazole treated and was formed in a rat
central venous catheter. Scale bar is 20 lm. Middle,C. neoformans
cells stained with India ink to highlight the capsule. Arrow indicates
the size of a titan cell as compared to a normal cell. Scale bar 10 lm.
Bottom,H. capsulatum can exist as either yeast or as mycelia. Scale
bar is 5 lm
Opportunistic yeast pathogens
123
required for dissemination throughout the body, while
filamentous cells are essential for penetrating tissues,
establishing infection and causing mortality [211]. A recent
study has shown that a clinical isolate locked in the yeast
form is more fit in a murine model of commensal infection
[212]. Furthermore, another recent study demonstrated that
cells locked in the yeast form are better able to colonize the
gastrointestinal tract in a mouse model, while constitu-
tively filamentous cells showed a decrease in colonization
[213]. Taken together, this demonstrates that the poly-
morphic nature of C. albicans is a key virulence trait that
allows it to adapt to the diverse conditions encountered
within the host.
While both yeast and filamentous morphologies con-
tribute to the pathogenesis of C. albicans, filamentous cells
do possess specific virulence characteristics that increase
their pathogenicity. For example, the sustained polarized
growth exhibited by a filamentous cell provides a physical
force that allows the fungal cell to penetrate host tissues,
allowing for further invasion of tissues and organs [214].
Hyphal cells also express Als3, a hypha-specific protein
found on the fungal cell surface [215]. Als3 is an adhesin
that mediates binding to host cells, and induces endocytosis
by binding to the host cell receptors E-cadherin and
N-cadherin [215]. Hwp1 is another hyphal-specific fungal
cell surface protein required to mediate attachment to ep-
ithelial cells [216]. In addition, the expression of genes
encoding secreted aspartyl proteinases (SAPs) is coordi-
nated with morphological state with SAP4 and SAP6 being
expressed by hyphal cells [217,218]. Additionally, con-
nections exist between C. albicans filamentation and drug
resistance. Certain proteins such as Hsp90 [219], O-man-
nosyltransferases [220], and the transcription factor Ndt80
[221] have roles in both morphogenesis and drug
resistance.
In addition to the striking morphological differences
between yeast and filamentous forms, C. albicans can
also undergo distinct phenotypic switches. One prominent
example is the switch between white and opaque cells.
The more common white cells have a round or oval
shape, while opaque cells are oblong and dimpled. This
transition is governed by the regulator Wor1, with ex-
pression of WOR1 leading to opaque cell formation
[222]. Opaque cells are mating competent, with progeny
showing recombination between chromosomes and alter-
ations in ploidy [223,224]. White and opaque cells show
distinct preferences for different host environments and
niches. Since opaque cells are not stable at 37 °C, they
preferentially colonize surface environments such as the
skin [225]. Furthermore, while white cells require the
elevated temperature of 37 °C for filamentation, opaque
cells filament preferentially at 25 °C[226]. Finally,
white-opaque switching may aid in the evasion of host
defenses, where white phase cells are preferentially rec-
ognized by neutrophils in certain environmental
conditions [227,228]. A novel phenotypic switch was
recently discovered upon passage of wild-type white cells
through the mouse gastrointestinal tract [117]. Induction
of WOR1 in this environment resulted in morphologically
and functionally distinct GUT (gastrointestinally induced
transition) cells, which are optimized for the digestive
tract. A third phenotypic variant, the ‘gray’ phenotype
has recently been identified [229]. This variant shows
elevated levels of SAP expression and the propensity to
colonize cutaneous tissue, similar to opaque cells. The
master regulators Wor1 and Efg1 may act coordinately to
regulate switching between white, gray and opaque cel-
lular states [229].
Distinct morphological transitions are also important
for virulence in C. neoformans (Fig. 1). While a typical
C. neoformans cell is approximately 5–10 lM, specific
conditions can induce the formation of titan cells, which
can be as large as 100 lM[230]. Distinct features of titan
cells include a thicker cell wall and denser capsule [231],
as well as a tetraploid or octaploid DNA content [230].
Although the exact mechanism for titan cell formation is
unclear, in part due to the difficulty in culturing titan cells
in vitro [232], several signaling pathways have been im-
plicated. The G protein-coupled receptors Ste3a (a
pheromone receptor) and Gpr5 are required for titan cell
production in vivo [170,230] as is signaling through the
cAMP/PKA pathway [170,231]. The Rim101 transcrip-
tion factor downstream of PKA signaling is also required
for titan cell production in vivo [170]. Titan cells play a
central role in C. neoformans pathogenicity, in that they
interact with the host immune system. The large size of
titan cells may prevent their phagocytosis [231,233]; titan
cells may also protect typical-sized cells from being
phagocytosed [233], and promote dissemination from the
lungs [234].
Biofilms
Biofilms are complex three-dimensional surface-associat-
ed communities of yeast and hyphal cells within an
extracellular matrix (ECM), and can be found on medical
devices such as catheters and artificial joints [235], or on
mucosal surfaces [236], contributing to virulence (Fig. 1).
The first step in biofilm formation is adherence to either
an abiotic or biotic surface. In C. albicans, cell wall ad-
hesins such as Eap1 and Als1, and other cell wall proteins
have roles in attachment of the biofilm to the surface,
which then stimulates changes in gene expression [237].
Adherence is followed by proliferation of yeast cells. This
basal layer of yeast cells may contribute to anchoring the
biofilm to the surface [238]. Next, yeast cells undergo the
E. J. Polvi et al.
123
morphogenetic transition to filamentous growth. The for-
mation of hyphae is important, as strains defective in
filamentation have a vastly reduced ability to form bio-
films, as with mutants lacking a major transcriptional
regulator of morphogenesis, Efg1 [238]. Accumulation of
the ECM is part of the biofilm maturation process. The
ECM is composed of mainly protein and carbohydrates,
including mannans and glucans; however, lipids and nu-
cleic acids are also found in the ECM [239]. Finally,
yeast cells are dispersed from the biofilm. These cells
have elevated pathogenicity, and an increased ability to
adhere [237].
Biofilms are notoriously difficult to treat with anti-
fungals, and have especially high levels of resistance to
azoles and polyenes [237]. Resistance to azoles is de-
pendent on the molecular chaperone Hsp90 [45], glucan
modification enzymes that are required for delivery and
organization of the ECM [240], and b-1,3 glucan in the
ECM that may sequester azoles [241]. Increased expres-
sion of efflux pumps early in biofilm development, and
the presence of persister cells also contribute to antifungal
resistance [242].
Secreted factors
Secretion of proteinases such as SAPs is crucial for both
pathogenesis and nutrient acquisition. As mentioned
above, C. albicans SAP4 and SAP6 expression is coor-
dinated with hyphal formation [217,218], while
expression of SAP1 is regulated by the white-to-opaque
phenotypic switch [243]. During infection, the SAP pro-
teins have roles in adherence to host cells [244] and
degradation of host proteins such as mucin [245], perhaps
allowing penetration and colonization of tissues. SAP
proteins may also degrade host antimicrobial factors such
as lactoferrin, complement and the proteinase inhibitor
cystatin A [244]. Secreted phospholipases cleave ester
linkages in glycophospholipids, and can have roles in host
cell penetration and invasion [246]. Mutants lacking the
phospholipase Plb1 have reduced virulence in a murine
model of Candida infection [247].
Histoplasma also secretes several factors important for
pathogenesis. The calcium-binding protein Cbp1 is se-
creted from yeast-phase H. capsulatum, and is required for
growth in calcium-depleted conditions and for virulence in
a murine model of pulmonary histoplasmosis [248].
Resolution of the structure by NRM revealed that Cbp1
may be a lipid-binding protein, and possibly interacts with
glycolipids in the host [249]. Yps3 is both a secreted factor
as well as a cell wall protein in H. capsulatum, and while
its exact function is yet to be elucidated, silencing of YPS3
results in reduced organ colonization in a murine model of
infection [250].
Evasion of the host immune system
Capsule and cell wall
The capsule of C. neoformans is an important virulence
determinant, playing key roles in surviving environ-
mental conditions and modulating the host immune
response (Fig. 1). The capsule is primarily composed of
the polysaccharides glucuronoxylomannan (GXM) and
glucuronoxylomannogalactan (GXMGal) [251]. Mono-
mers of simple sugars are modified and polymerize
within the cell before being secreted and attached to the
cell wall surface. An important modification of capsule
monomers is xylosylation, such that deletion of the
xylosyltransferase gene CXT1 results in an altered cap-
sule structure and reduced virulence [252].
O-acetylation contributes to the antigenicity of the
capsule by affecting binding of antibodies and activation
of the complement cascade [253]. Hyaluronic acid,
synthesized by Cps1, is also added to the capsule and
may play a role in facilitating passage of C. neoformans
across the blood–brain barrier [254]. Finally, antigenic
variation of capsule monomers can lead to differential
binding of antibodies [255].
Just as conditions that mimic physiologically relevant
host conditions induce filamentation in C. albicans,
similar cues also induce capsule formation in C.
neoformans. Upon infection of a host, the capsule in-
creases in size with the thickness being determined by
the location of infection. Infection of the lungs results in
a thicker capsule than does infection of the brain [256],
demonstrating that regulation of capsule synthesis is
dependent on the environmental niche. Nutrient-poor
conditions such as low glucose and low nitrogen can
contribute to capsule induction by signaling through the
cAMP–PKA pathway [257–259]. Similarly, as iron
levels are tightly controlled within the host, conditions
of low iron are a potent inducer of capsule formation
[260]. The iron-sensing transcription factor Cir1 is one
of the main regulators of capsule induction in response
to iron poor conditions [183]. Induction of capsule for-
mation in low iron conditions is also signaled through
the cAMP–PKA pathway [251]. Additionally, the cAMP
pathway is used to signal capsule formation in the
presence of high CO
2
levels [251,261]. Physiological
pH is another cue that is sensed by C. neoformans to
regulate capsule formation, and the conserved Rim101
pH-sensing pathway integrates signals from the cAMP–
PKA pathway to regulate attachment of the capsule to
the fungal cell wall [169]. However, it appears that al-
kaline pH alone is insufficient to induce an enlarged
capsule, and instead this condition must be combined
with others, such as nutrient deprivation or the presence
Opportunistic yeast pathogens
123
of serum [262]. Finally, stress response pathways can
havearepressiveeffectoncapsule induction, such as
the Hog1 and protein kinase C (PKC) pathways that
respond to osmotic stress [251].
The capsule is essential for C. neoformans interactions
with the host immune system. The polysaccharides GXM
and GXMGal have immunosuppressive properties such as
modulation of macrophage, neutrophil and dendritic cell
activities, and also inhibition of pro-inflammatory cytokine
production [263]. GXMGal reduces B cell activity and
inhibits activation of T cells. The capsule also has an-
tiphagocytic properties, inhibiting phagocytosis in vitro
due to the large size of the capsule, and possibly by hiding
pathogen-associated molecular patterns (PAMPs) on the
cell surface [264].
To avoid interaction with host phagocytes that would
initiate the production of reactive oxygen species and the
secretion of pro-inflammatory cytokines, H. capsulatum
antigenic cell surface bglucans are hidden under a layer of
a-(1,3)-glucan. Silencing of AGS1, encoding the a-glucan
synthase, severely attenuates virulence of H. capsulatum in
mouse lungs [265]. Loss of a-(1,3)-glucan allows for
recognition of the bglucans by the host receptor dectin-1
[266]. Additionally, heat shock protein 60 (HSP60) on the
cell surface binds to the CR3 receptor on macrophages,
followed by phagocytosis [267]. However, interactions
with CR3 do not typically result in a strong immune re-
sponse unless other costimulatory signals are present [268,
269], allowing H. capsulatum to grow and survive within
macrophages.
Escape from macrophages
Fungi have evolved multiple mechanisms to avoid being
killed upon phagocytosis by immune cells such as mac-
rophages. One mechanism is to escape the phagocyte,
either by inducing macrophage lysis or by non-lytic
exocytosis. Non-lytic expulsion of fungal cells was first
described in C. neoformans, where live yeasts were able
to escape macrophages without killing the host cell [270–
272]. This prevents release of pro-inflammatory cytokines
and potentially aids in transversal of cryptococcal cells
across the blood–brain barrier [105]. This phenomenon of
non-lytic expulsion has also been observed in C. albicans,
although at lower frequency than for C. neoformans
[273]. Candida albicans can also escape from macro-
phages via filamentation. These filaments can induce
pyroptosis, a programmed pro-inflammatory macrophage
death [274,275]. This process is hypothesized to be de-
pendent on the transition to hyphae, which stimulate host
pyroptotic caspases and result in macrophage death [274,
275].
Nitric oxide detoxification
Nitric oxide (NO) is a nitrogen radical and antimicrobial
effector produced by the host immune system in response
to fungal infections. Candida albicans responds to this
stress by increasing the expression of an NO dioxygenase
flavohemoglobin, YHB1 [276,277], which metabolizes
NO. Candida albicans cells lacking YHB1 have increased
sensitivity to NO and reduced virulence in a murine model
of systemic candidiasis [276,277].
Cryptococcus neoformans also employs an enzymatic
defense against NO produced by the host. The flavohe-
moglobin denitrosylase Fhb1 consumes NO, and cells in
which FHB1 is disrupted have reduced survival in mac-
rophages and decreased virulence in a murine inhalation
model [278]. A global analysis of the C. neoformans re-
sponse to nitrosative stress revealed that the glutathione
reductase Glr1 is upregulated in response to NO [279].
Deletion of GLR1 renders C. neoformans sensitive to ni-
trosative stress, and avirulent in a mouse inhalation model
[279].
Although the presence of a flavohemoglobin in H.
capsulatum is not apparent, a shotgun genomic microarray
did identify NOR1, a P450 nitric oxide reductase homo-
logue, whose expression is increased by nitrosative stress
[280]. Overexpression of this gene decreased the sensitivity
of H. capsulatum to reactive nitrogen species [280].
Melanin
In C. neoformans, melanins are pigmented molecules with
antioxidant properties, synthesized by the laccase enzymes
Lac1 and Lac2 [264]. Melanization occurs during infection
[281], and overexpression of melanin results in decreased
recognition by the host and modulation of host cell immune
responses [282]. Melanized cells are also less susceptible to
microbicidal peptides and recognition by macrophages, as
well as being less susceptible to antifugal drugs in vitro
[283]. Together, this demonstrates an important role for
melanin in the virulence of C. neoformans.
Urea metabolism
In addition to being used as a nitrogen source by many
fungi, C. albicans and C. neoformans also use urea meta-
bolism to modulate the host immune system and alter
dissemination [284]. Urease is considered a cryptococcal
virulence factor as urease expression is linked with in-
creased invasion across the blood–brain barrier [285],
increased fungal burden, and altered host immune re-
sponses [286–288]. Urease-positive C. neoformans induce
a strong non-protective Th2 response as demonstrated by
E. J. Polvi et al.
123
an increased accumulation of eosinophils in the lung, in-
creased serum IgE and higher levels of Th2 cytokines
[288], demonstrating a role for urease in influencing the
host immune response.
While C. albicans does not contain a urease enzyme, it
does contain a urea amidolyase, encoded by DUR1,2 [289].
Deletion of DUR1,2 results in cells that are less virulent
than wild-type cells in a murine model of disseminated
candidiasis and results in decreased kidney fungal burden
[290]. Additionally, deletion of DUR1,2 causes a decreased
inflammatory response in the kidneys, reduced neutrophil
infiltration and altered host cytokine and chemokine pro-
duction, suggesting a role for urea metabolism in
modulating host immune responses [290]. A dur1,2 mutant
also shows impaired escape from host macrophages as it is
unable to form filaments in the presence of urea or argi-
nine, a urea-precursor [291]. This may be coupled to the
defect of the dur1,2 strain in auto-alkalinization of the
environment [174].
Host immune responses
The interactions between opportunistic fungal infections
and the host immune system are complex and only be-
ginning to be understood. Outcomes of infections are
dependent on interactions between the host immune re-
sponse and the intrinsic virulence of the pathogen.
Opportunistic fungi such as C. albicans constantly in-
teract with the host immune system, and perturbations to
this balance can result in a switch from commensalism
to pathogenesis, as discussed above. Alterations to the
innate or adaptive host immune responses, either due to
immunosuppression or genetic predisposition, can result
in severe and often deadly fungal infections. The inter-
play between fungi and the host immune system has
been the subject of several recent reviews [8,292–294].
Here we summarize this interaction, and describe host
factors that can increase susceptibility to fungal
infections.
Host response to fungal pathogens
Innate
Physical barriers such as the skin and mucosal epithelial
cells at sites continuously in contact with fungal pathogens
are the first line of defense against fungal pathogens. The
next barrier is the innate immune response, which is crucial
for preventing invasive and systemic infections. The innate
immune response is required for recognition of fungal
PAMPs. The fungal cell wall is composed of many
PAMPs, including both a- and b-glucans, chitin, chitosan,
and mannans [295]. These PAMPs can be recognized by
host pattern recognition receptors (PRRs) on phagocytic
cells such as macrophages, dendritic cells and neutrophils
[292,293]. Specific PAMPs on different fungal species can
be recognized by specific PRRs, including complement
components, toll-like receptors (TLRs), C-type lectin re-
ceptors (CLRs), and mannose receptors (MR), among
others [296–299]. These interactions will shape the re-
sulting immune response, including phagocytosis of the
pathogen, production of inflammatory cytokines, and acti-
vation of T cells.
Upon phagocytosis, fungal cells can be killed by ef-
fector molecules such as proteases, defensins, and cationic
peptides as well as by the production of reactive oxygen
and nitrogen species [294]. Neutrophils are highly effective
at containing fungal infections, including inhibition of the
C. albicans morphological transition [300]. Neutropenic
patients, including those with acute leukemia, are at high
risk of developing invasive Candida and Aspergillus in-
fections, and are often given prophylactic antifungal
therapies as a preventative measure [301]. However, in-
creased neutrophils in mouse kidneys are associated with
pathogenesis of C. albicans at late time points [302].
Adaptive
The adaptive immune system involves stimulation of T
cells by antigen-presenting cells [292,303]. These antigen-
presenting cells can generate specific cytokine profiles that
can bias the immune system towards Th1-, Th2-, Treg-, or
Th17-responses [303]. The balance between these re-
sponses is crucial for the ability to clear the pathogen
without causing autoimmune damage.
The adaptive immune response plays a pivotal role in
preventing fungal infections, as highlighted by the inci-
dence of fungal disease in AIDS patients [10,304]. HIV
infection depletes the pool of CD4
?
T cells, consequently
causing a loss of antifungal immunity. This results in im-
paired production of interferon-c(IFN-c) and tumor
necrosis factor-a(TNF-a)[304]. Additionally, the
population of memory B cells is depleted [305], and
macrophage and dendritic cell function is impaired upon
HIV infection [306], contributing to increased suscepti-
bility to fungal infections.
Th1 responses include the production of IFN-c, which is
key for controlling many disseminated fungal infections
[303]. Cryptococcus neoformans strains that induce Th1-
biased responses are generally cleared from the lung and do
not cause disease [307,308]. The decrease in Th1-type
cell-mediated immune responses in AIDS patients may
explain their increased susceptibility to cryptococcal in-
fections compared to patients with other types of immune
deficiencies [309].
Opportunistic yeast pathogens
123
Th17 responses appear to be critical for host defense
against fungal infections, especially Candida [310]. In HIV
patients, susceptibility to mucosal candidiasis can be at-
tributed to a loss of mucosal Th17 cells, which is
accompanied by a decrease in the integrity of epithelial
cells and alterations to the intestinal environment [311].
Decreases in the Th17 response also leads to increased
severity of Pneumocystis infections in mice [312].
Regulatory T (Treg) cells continually survey the host for
signs of mucosal infections and aid in preventing reinfec-
tion. However, Treg cells are able to suppress inflammation
during systemic candidiasis by producing interleukin 4 (IL-
4), IL-10, and transforming growth factor-b(TGF-b),
which inhibit inflammatory Th1 and Th17 responses
making them detrimental for clearing the infection [313].
Depletion of Treg cells results in decreased C. albicans
growth in a murine model of candidiasis [313], and a de-
crease in Treg cells is also associated with an increase in
the Th17 responses that are beneficial in clearing Histo-
plasma infections [314].
In contrast, Th2 responses to fungal infections are often
deleterious [292]. During C. neoformans infections, the
fungi are able to induce a strong Th2-biased immune re-
sponse, with increased levels of IL-4 and IL-5, thus
favoring persistence of the infection [309]. Mice with in-
creased IL-4 levels also demonstrated increased
Histoplasma infections [315]. In addition to favoring per-
sistence of the infection, Th2 responses are also linked with
allergic bronchopulmonary aspergillosis and increased
susceptibility to invasive aspergillosis [316]. In contrast,
Th2 responses may be protective against Pneumocystis
pneumonia, with affected HIV individuals showing low
levels of Th2 cytokines [317].
Immune reconstitution inflammatory syndrome
The recovered immune system in AIDS patients treated
with antiretrovirals can overreact to PAMPs exposed dur-
ing fungal infections, even if the infections have been
cleared by antifungal therapies. This overactive inflam-
mation is known as immune reconstitution inflammatory
syndrome (IRIS), and it can cause significant mortality due
to damage by the host immune system. IRIS is a major
consideration in the treatment of AIDS patients with
cryptococcosis. Recent studies have noted that between 8
and 50 % of AIDS patients develop cryptococcal IRIS,
even when no live cryptococcal cells are recovered from
the patient [35,318]. IRIS can also occur in transplant
patients after reduction in the immunosuppresive therapies
used to prevent organ rejection [319]. The inflammatory
immune response in these IRIS patients consists of in-
creased IL-6 and C-reactive protein (CRP) levels.
Additionally, many patients who go on to develop IRIS
have decreased TNF-aand other Th1 cytokines prior to
antiretroviral therapy [320]. The current standard of care
for IRIS patients includes administration of steroids to
decrease systemic inflammatory responses and prevent
further damage to host tissues [36,90].
Genetic susceptibility to fungal infections
Chronic mucocutaneous candidiasis
Recurrent Candida infections of cutaneous or mucosal
surfaces in the absence of immunosuppressive conditions
(such as HIV), is described as chronic mucocutaneous
candidiasis (CMC). IL-17 signaling and activation of T
cells are essential for defending against mucocutaneous C.
albicans infections and genetic mutations that perturb this
signaling pathway can lead to CMC [321].
Numerous single nucleotide polymorphisms have been
associated with increased susceptibility to CMC (see [8,
292,321]). For example, loss of function of the CLR
dectin-1 can lead to increased onychomycosis and muco-
cutaneous candidiasis [322,323]. This is the result of
defective recognition of bglucan in the C. albicans cell
wall and impaired cytokine production (including IL-1b
[323] and IL-17 [322]). Neutrophil function remains
unaffected, and thus systemic candidiasis is not associated
with dectin-1 mutations [323]. The caspase recruitment
domain-containing protein 9 (CARD9) is a signaling pro-
tein downstream of many CLRs, including dectin-1 [321]
and activates the nuclear factor-jB (NF-jB) pathway
[324]. Autosomal recessive mutations in CARD9 can result
in decreased development of Th17 cells and is associated
with CMC [324]. Autosomal dominant gain-of-function
mutations such as those in STAT1 (signal transducer and
activator of transcription 1) can also lead to inhibition of
Th17 development, and increased susceptibility to CMC
[325,326]. Additionally, autosomal recessive mutations in
the IL-17 receptor IL-17RA, and deficiencies in the cy-
tokine IL-17F can result in CMC [327]. Mice with deficient
IL-17A production show an impaired ability to clear a
cutaneous C. albicans infection [328], suggesting that both
IL-17A and IL-17F are required for the defense against
chronic mucocutaneous candidiasis.
Additional syndromes can lead to CMC. One of these is
hyper-IgE syndrome (HIES), in which patients experience
recurrent pulmonary infections, eczema, staphylococcal
infections, and CMC, among other symptoms. Mutations in
STAT3 have been identified as a cause of HIES [329], in
which an inability of CD4
?
T lymphocytes to differentiate
into Th17 cells results in impaired IL-17 production [330].
Mutations in DOCK8 (dedicator of cytokinesis 8) have been
identified in the autosomal recessive form of this syndrome,
in which there is defective T cell activation and Th17 cell
E. J. Polvi et al.
123
differentiation [331]. Finally, the rare autoimmune
polyendocrinopathy–candidiasis–ectodermal dystrophy
(APECED) syndrome is characterized by development of
CMC in almost all patients, and is caused by mutations in
the autoimmune regulator AIRE [321,332]. The strong
prevalence of CMC in these patients may be due to the
production of neutralizing autoantibodies against Th17-
produced cytokines, specifically IL-17A, IL-17F and IL-22
[333].
Invasive fungal infections
While mucocutaneous Candida infections are primarily
caused by defects in the adaptive immune system, defi-
ciencies in the innate immune response, such as those
caused by primary immunodefiencies can lead to invasive
yeast infections. A few such cases are outlined below.
Chronic granulomatous disease (CGD) is the result of
mutations in genes encoding components of the NADPH
oxidase complex, impairing the ability of phagocytes to
produce reactive oxygen species [334]. While the primary
fungal infection associated with CGD is invasive
aspergillosis, [335] infections by Candida and Tri-
chosporon species have also been noted [321].
Myeloperoxidase (MPO) deficiency is a disorder in which
the production of antimicrobial hypochlorous acid by
phagocytic cells is impaired, and mice deficient for either
NADPH or MPO show increased mortality in response to a
high dose of C. albicans [336]. While the majority of MPO
patients do not suffer from fungal infections, those who do
acquire infections usually also have diabetes [337]. Patients
presenting with monocytopenia are more susceptible to
histoplasmosis and cryptococcal infections [338], and
cryptococcosis has also been observed in patients with
hyper-IgE or hyper-IgM syndromes and idiopathic CD4
lymphocytopenia [321]. Finally, patients with severe
combined immunodeficiency commonly acquire Pneumo-
cystis pneumonia, as do those with hyper-IgM syndrome
[321].
Management of fungal infections
Diagnosis
The first step in achieving the proper management of in-
fectious disease is the effective diagnosis and species
identification of the pathogen. Unfortunately, shortcomings
in current diagnostic techniques remain one of the greatest
challenges in the field. In most cases, diagnosis still relies
on traditional culture methods and histopathology [10,87,
339,340]. Culturing the organism and subsequent identi-
fication is a slow process that takes several days, leading to
considerable delays in treatment. Such delays have direct
and significant impact on disease outcome and patient
mortality, especially for severe invasive diseases [136,
340]. A number of novel molecular diagnostic approaches
have been developed to improve the current system, in-
cluding PCR-based assays and antigen detection systems
[339,341]. However, these are not regular practice in the
clinic, and still need to be standardized and tested in large
patient cohorts before they can be incorporated into clinical
guidelines [87,90,110,339].
Antifungal drugs
Due to the close evolutionary relatedness between humans
and fungi, the number of targets that can be selectively
exploited for drug development is limited [10,342]. There
are also very few drugs currently being developed, pri-
marily because antifungals are not predicted to generate a
large enough financial return for pharmaceutical companies
[10]. Polyenes, azoles, and echinocandins represent the
three most common classes of antifungals currently used in
the clinic, each with their own advantages and limitations.
Overall, host toxicity, cross reactivity with other drugs, and
development of drug resistance pose great challenges to
current antifungals.
Polyenes
Polyenes are broad-spectrum natural product antifungals
discovered in the early 1950s from the bacterial genus
Streptomyces [342,343]. Polyenes bind to ergosterol in the
fungal membrane, generating aqueous pores that result in
leakage of fungal cell content and eventually cell death
[344,345]. Amphotericin B, one of the most successful
polyene derivatives, was a gold standard in treating serious
fungal infections. However, amphotericin B is known to
cause severe systemic toxicity and nephrotoxicity [342,
346]. Various drug delivery systems have been developed
to improve its safety profile, including the popular lipid
formulation [347,348]. While its clinical use decreased
with the development of azoles in the late 1980s, it is still
widely deployed to treat life-threatening disseminated and
invasive mycoses [90,110]. Fortunately, despite its long
history of clinical use, resistance to polyenes remains a rare
occurrence [349,350].
Azoles
Azoles are synthetic compounds that were first introduced
as antifungals in the late 1980s and early 1990s [344].
Their low toxicity led to extensive use in the clinic. Azoles
disrupt the biosynthesis of ergosterol by inhibiting the
cytochrome P-450-dependent enzyme lanosterol
Opportunistic yeast pathogens
123
demethylase (also referred to as 14a-sterol demethylase)
[351]. Azoles are chemically classified as either imidazoles
if they have two nitrogen atoms in the azole ring, or tria-
zoles if they have three [343,351]. Imidazoles are typically
limited to topical treatment of superficial infections, while
triazoles are used more broadly in both superficial and
systemic infections due to their superior pharmacokinetic
and safety profile. The most commonly used azoles in the
clinic include fluconazole, itraconazole, voriconazole, and
posaconazole.
Azoles remain the drug of choice as initial therapy for
most fungal infections and are often recommended as
prophylaxis for high-risk patients [90,110,352]. Wide-
spread use of azoles has led to increasing reports of azole
resistance in the clinic, which is associated with greater
treatment difficulties and patient mortality [353]. There has
also been an increased incidence of infections caused by
intrinsically azole-resistant fungal species, including C.
glabrata and C. krusei, creating major challenges for future
treatments [87].
Echinocandins
Echinocandins first entered the market in 2001, represent-
ing the newest class of antifungals to reach the clinic [354].
Echinocandins are large semi-synthetic lipopeptides that
inhibit the cell wall enzyme complex b-1,3-D-glucan syn-
thase [355], thereby decreasing the concentration of b-
(1,3)-glucan in the fungal cell wall and causing the sub-
sequent loss of cell wall integrity. Echinocandins are
generally well tolerated with little to no side effects [356].
Echinocandins are active against Candida and Asper-
gillus species, including azole-resistant Candida isolates,
but show no in vivo activity against Cryptococcus [90,110,
342]. Currently available echinocandins include caspo-
fungin, anidulafungin, and micafungin [354]. All three are
not orally bioavailable and need to be administered intra-
venously. Echinocandin resistance has been reported in the
clinic, and the incidence appears to be on the rise [357].
Vaccines
An ideal solution to fungal management is the prevention
of disease through vaccination. However, there is currently
no clinically available vaccine for any fungal pathogen.
Over the years, a number of vaccines have been in devel-
opment against different fungi, with promising results in
animal models [10,358]. However, only a few have been
translated to human clinical trials, with the major barrier
being the lack of funding [359]. Efficacy trials are also
difficult to conduct as high-risk patients often routinely
receive antifungal prophylaxis [10]. Nonetheless, two
subunit vaccines against Candida have recently
demonstrated success in Phase I clinical trials, one of
which is currently being tested in a Phase II trial in the
United States [360]. This vaccine represents a promising
advance and may stimulate further development of much
needed immunotherapeutics and vaccines [358,361,362].
Concluding remarks
A significant advance in our understanding of invasive
fungal infections has been made in recent years, motivated
at least in part by the increasing incidence of these infec-
tions. Given the growing number of transplant patients,
those in receipt of immunosuppressive therapy and the
global HIV pandemic, this comes as no surprise. Host
niches are complex, dynamic and distinct to each indi-
vidual, as are the pathogens’ response strategies for
coexisting with or evading the host immune response.
Taking steps towards understanding the underlying im-
munopathogenesis of fungal infections permits early and
accurate diagnosis and treatment. We must continue to
seek out novel diagnostics that will allow for rapid treat-
ment of fungal infections with the appropriate antifungal.
With the rise in antifungal drug resistance now a real
threat, researchers must strive to discover novel antifungals
and antifungal drug combinations, as well as effective
immunotherapeutic strategies that combat resistance, im-
prove patient outcome, shorten hospital stays and ease the
economic burden.
Acknowledgments We thank the J. Andrew Alspaugh and Chad
Rappleye labs for images and Cowen lab members for helpful dis-
cussions. EJP is supported by a Canadian Institutes of Health
Research (CIHR) Frederick Banting and Charles Best CGS Doctoral
Award, XL by a University of Toronto Fellowship, MDL by a Sir
Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072),
and LEC by a Ministry of Research and Innovation Early Researcher
Award, Canada Research Chair in Microbial Genomics and Infectious
Disease, Natural Sciences and Engineering Research Council Dis-
covery Grant #355965, and by Canadian Institutes of Health Research
Grants MOP-86452 and MOP-119520.
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