species are common colonizers of the human skin, vagina, and the gut. As human commensals,
species do not cause any notable damage in healthy individuals; however, in certain conditions they can ...initiate a wide range of diseases such as chronic disseminated candidiasis, endocarditis, vaginitis, meningitis, and endophthalmitis. The incidence of
caused infections has increased worldwide, with mortality rates exceeding 70% in certain patient populations.
, and
are responsible for more than 90% of
-related infections. Interestingly, the host immune response against these closely related fungi varies. As part of the innate immune system, complement proteins play a crucial role in host defense, protecting the host by lysing pathogens or by increasing their phagocytosis by phagocytes through opsonization. This review summarizes interactions of host complement proteins with pathogenic
species, including
and non
species such as
. We will also highlight the various ways of complement activation, describe the antifungal effects of complement cascades and explore the mechanisms adopted by members of pathogenic
species for evading complement attack.
Abstract
In recent years, the relevance of diseases associated with fungal pathogens increased worldwide. Members of the Candida genus are responsible for the greatest number of fungal bloodstream ...infections every year. Epidemiological data consistently indicate a modest shift toward non-albicans species, albeit Candidaalbicans is still the most recognizable species within the genus. As a result, the number of clinically relevant pathogens has increased, and, despite their distinct pathogenicity features, the applicable antifungal agents remained the same. For bloodstream infections, only three classes of drugs are routinely used, namely polyenes, azoles and echinocandins. Antifungal resistance toward all three antifungal drug classes frequently occurs in clinical settings. Compared with the broad range of literature on virulence and antifungal resistance of Candida species separately, only a small portion of studies examined the effect of resistance on virulence. These studies found that resistance to polyenes and echinocandins concluded in significant decrease in the virulence in different Candida species. Meanwhile, in some cases, resistance to azole type antifungals resulted in increased virulence depending on the species and isolates. These findings underline the importance of studies aiming to dissect the connections of virulence and resistance in Candida species.
The authors discuss how the rising clinical relevance of fungal infections to the understanding of antifungal resistance development and its effects on the virulence attributes of pathogens could be highly beneficial, as it could lead to more efficient therapeutic practice.
Patients with suppressed immunity are at the highest risk for hospital-acquired infections. Among these, invasive candidiasis is the most prevalent systemic fungal nosocomial infection. Over recent ...decades, the combined prevalence of non-
species outranked
infections in several geographical regions worldwide, highlighting the need to understand their pathobiology in order to develop effective treatment and to prevent future outbreaks.
is the second or third most frequently isolated
species from patients. Besides being highly prevalent, its biology differs markedly from that of
, which may be associated with
' increased incidence. Differences in virulence, regulatory and antifungal drug resistance mechanisms, and the patient groups at risk indicate that conclusions drawn from
pathobiology cannot be simply extrapolated to
Such species-specific characteristics may also influence their recognition and elimination by the host and the efficacy of antifungal drugs. Due to the availability of high-throughput, state-of-the-art experimental tools and molecular genetic methods adapted to
, genome and transcriptome studies are now available that greatly contribute to our understanding of what makes this species a threat. In this review, we summarize 10 years of findings on
pathogenesis, including the species' genetic properties, transcriptome studies, host responses, and molecular mechanisms of virulence. Antifungal susceptibility studies and clinician perspectives are discussed. We also present regional incidence reports in order to provide an updated worldwide epidemiology summary.
Oral squamous cell carcinoma (OSCC) is associated with oral Candida albicans infection, although it is unclear whether the fungus promotes the genesis and progression of OSCC or whether cancer ...facilitates fungal growth. In this study, we investigated whether C. albicans can potentiate OSCC tumor development and progression.
, the presence of live C. albicans, but not Candida parapsilosis, enhanced the progression of OSCC by stimulating the production of matrix metalloproteinases, oncometabolites, protumor signaling pathways, and overexpression of prognostic marker genes associated with metastatic events. C. albicans also upregulated oncogenes in nonmalignant cells. Using a newly established xenograft
mouse model to investigate OSCC-C. albicans interactions, oral candidiasis enhanced the progression of OSCC through inflammation and induced the overexpression of metastatic genes and significant changes in markers of the epithelial-mesenchymal transition. Finally, using the 4-nitroquinoline 1-oxide (4NQO) murine model, we directly correlate these
and short-term
findings with the progression of oncogenesis over the long term. Taken together, these data indicate that C. albicans upregulates oncogenes, potentiates a premalignant phenotype, and is involved in early and late stages of malignant promotion and progression of oral cancer.
Oral squamous cell carcinoma (OSCC) is a serious health issue worldwide that accounts for 2% to 4% of all cancer cases. Previous studies have revealed a higher yeast carriage and diversity in oral cancer patients than in healthy individuals. Furthermore, fungal colonization in the oral cavity bearing OSCC is higher on the neoplastic epithelial surface than on adjacent healthy surfaces, indicating a positive association between oral yeast carriage and epithelial carcinoma. In addition to this, there is strong evidence supporting the idea that
contributes to carcinogenesis events in the oral cavity. Here, we show that an increase in Candida albicans burden promotes an oncogenic phenotype in the oral cavity.
Convergent evolution is common throughout the tree of life, but the molecular mechanisms causing similar phenotypes to appear repeatedly are obscure. Yeasts have arisen in multiple fungal clades, but ...the genetic causes and consequences of their evolutionary origins are unknown. Here we show that the potential to develop yeast forms arose early in fungal evolution and became dominant independently in multiple clades, most likely via parallel diversification of Zn-cluster transcription factors, a fungal-specific family involved in regulating yeast-filamentous switches. Our results imply that convergent evolution can happen by the repeated deployment of a conserved genetic toolkit for the same function in distinct clades via regulatory evolution. We suggest that this mechanism might be a common source of evolutionary convergence even at large time scales.
Candida parapsilosis and Candida albicans are human fungal pathogens that belong to the CTG clade in the Saccharomycotina. In contrast to C. albicans, relatively little is known about the virulence ...properties of C. parapsilosis, a pathogen particularly associated with infections of premature neonates. We describe here the construction of C. parapsilosis strains carrying double allele deletions of 100 transcription factors, protein kinases and species-specific genes. Two independent deletions were constructed for each target gene. Growth in >40 conditions was tested, including carbon source, temperature, and the presence of antifungal drugs. The phenotypes were compared to C. albicans strains with deletions of orthologous transcription factors. We found that many phenotypes are shared between the two species, such as the role of Upc2 as a regulator of azole resistance, and of CAP1 in the oxidative stress response. Others are unique to one species. For example, Cph2 plays a role in the hypoxic response in C. parapsilosis but not in C. albicans. We found extensive divergence between the biofilm regulators of the two species. We identified seven transcription factors and one protein kinase that are required for biofilm development in C. parapsilosis. Only three (Efg1, Bcr1 and Ace2) have similar effects on C. albicans biofilms, whereas Cph2, Czf1, Gzf3 and Ume6 have major roles in C. parapsilosis only. Two transcription factors (Brg1 and Tec1) with well-characterized roles in biofilm formation in C. albicans do not have the same function in C. parapsilosis. We also compared the transcription profile of C. parapsilosis and C. albicans biofilms. Our analysis suggests the processes shared between the two species are predominantly metabolic, and that Cph2 and Bcr1 are major biofilm regulators in C. parapsilosis.
Eicosanoids are bioactive lipid mediators generated in almost all mammalian cells from the oxidation of arachidonic acid and other related twenty-carbon polyunsaturated fatty acids (PUFA). ...Eicosanoids regulate various physiological functions, including cellular homoeostasis and modulation of inflammatory responses in mammals. The mode of action of these lipid mediators depend on their binding to different G-protein coupled receptors. The three main enzymatic pathways associated with their production are the COX pathway, LOX pathway and cytochrome P450 pathway. Interestingly, investigations have also revealed that several human pathogenic fungi are capable of producing these bioactive lipid mediators; however, the exact biosynthetic pathways and their function in pathogenicity are not yet extensively characterized. The aim of the current review is to summarize the recent discoveries pertaining to eicosanoid production by human pathogenic yeasts with a special focus on the opportunistic human fungal pathogen Candida parapsilosis.
The Candida parapsilosis species complex comprises a group of emerging human pathogens of varying virulence. This complex was recently subdivided into three different species: C. parapsilosis sensu ...stricto, C. metapsilosis, and C. orthopsilosis. Within the latter, at least two clearly distinct subspecies seem to be present among clinical isolates (Type 1 and Type 2). To gain insight into the genomic differences between these subspecies, we undertook the sequencing of a clinical isolate classified as Type 1 and compared it with the available sequence of a Type 2 clinical strain. Unexpectedly, the analysis of the newly sequenced strain revealed a highly heterozygous genome, which we show to be the consequence of a hybridization event between both identified subspecies. This implicitly suggests that C. orthopsilosis is able to mate, a so-far unanswered question. The resulting hybrid shows a chimeric genome that maintains a similar gene dosage from both parental lineages and displays ongoing loss of heterozygosity. Several of the differences found between the gene content in both strains relate to virulent-related families, with the hybrid strain presenting a higher copy number of genes coding for efflux pumps or secreted lipases. Remarkably, two clinical strains isolated from distant geographical locations (Texas and Singapore) are descendants of the same hybrid line, raising the intriguing possibility of a relationship between the hybridization event and the global spread of a virulent clone.
Among all the essential micronutrients, iron plays an important role in mammalian biology. It is also essential for pathogens infecting mammalian hosts, including bacteria, fungi, and protozoans. As ...the availability of accessible iron is limited within the mammalian host, several human-pathogenic fungal pathogens, such as
,
,
, and
, have developed various iron uptake mechanisms. Although
is the second or third most common non-
species associated with systemic and superficial
infections in immunocompromised patients, the mechanisms of iron uptake and homoeostasis remain unknown in this fungus. In the current report, we show that a homologue of the multicopper oxidase gene
is present in the genome of
(
) and plays a significant role in iron acquisition. We found that homozygous deletion mutants of
showed defects under low-iron conditions and were also sensitive to various stressors. Our results also revealed that the levels of pseudohypha formation and biofilm formation were reduced in the null mutants compared to the wild type. This phenotypic defect could be partially rescued by supplementation with excess iron in the growth medium. The expression levels of the orthologues of various iron metabolism-related genes were also altered in the mutants compared to the parental strain. In conclusion, our report describes the role of
in iron homoeostasis maintenance as well as morphology and biofilm formation regulation in this pathogenic fungus.
is the second or third most common opportunistic human-pathogenic
species, being responsible for severe fungal infections among immunocompromised patients, especially low-birth-weight infants (0 to 2 years of age). Among the major virulence factors that pathogenic fungi possess is the ability to compete with the host for essential micronutrients, including iron. Accessible iron is required for the maintenance of several metabolic processes. In order to obtain accessible iron from the host, pathogenic fungi have developed several iron acquisition and metabolic mechanisms. Although
is a frequent cause of invasive candidiasis, little is known about what iron metabolic processes this fungus possesses that could contribute to the species' virulent behavior. In this study, we identified the multicopper oxidase
gene that regulates iron homeostasis maintenance and also plays important roles in the morphology of the fungus as well as in biofilm formation, two additional factors in fungal virulence.
PDF
