fungi pathogenic to humans-candida, aspergillus, cryptococcus

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Fungi pathogenic to humans: molecular basisof virulence of Candida albicans, Cryptococcus

neoformans and Aspergillus fumigatus. Acta

Biochim Pol

Article in Acta biochimica Polonica · July 2009

Impact Factor: 1.15 · Source: PubMed

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3 authors, including:

Justyna Karkowska-Kuleta

Jagiellonian University

12 PUBLICATIONS 196 CITATIONS

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Maria Rapala-Kozik

Jagiellonian University

37 PUBLICATIONS 584 CITATIONS

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https://www.researchgate.net/profile/Justyna_Karkowska-Kuleta?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_1https://www.researchgate.net/profile/Maria_Rapala-Kozik2?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_7https://www.researchgate.net/institution/Jagiellonian_University?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_6https://www.researchgate.net/profile/Maria_Rapala-Kozik2?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_5https://www.researchgate.net/profile/Maria_Rapala-Kozik2?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_4https://www.researchgate.net/profile/Justyna_Karkowska-Kuleta?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_7https://www.researchgate.net/institution/Jagiellonian_University?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_6https://www.researchgate.net/profile/Justyna_Karkowska-Kuleta?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_5https://www.researchgate.net/profile/Justyna_Karkowska-Kuleta?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_1https://www.researchgate.net/publication/26308247_Fungi_pathogenic_to_humans_molecular_basis_of_virulence_of_Candida_albicans_Cryptococcus_neoformans_and_Aspergillus_fumigatus_Acta_Biochim_Pol?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_3https://www.researchgate.net/publication/26308247_Fungi_pathogenic_to_humans_molecular_basis_of_virulence_of_Candida_albicans_Cryptococcus_neoformans_and_Aspergillus_fumigatus_Acta_Biochim_Pol?enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk%3D&el=1_x_2


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Review

Fungi pathogenic to humans: molecular bases of virulence of Candidaalbicans, Cryptococcus neoformans and Aspergillus fumigatus*

Justyna Karkowska-Kuleta , Maria Rapala-Kozik and Andrzej Kozik

Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics, and Biotechnology, JagiellonianUniversity, Kraków, Poland

Received: 07 April, 2009; revised: 06 June, 2009; accepted: 17 June, 2009

available on-line: 18 June, 2009

The frequency of severe systemic fungal diseases has increased in the last few decades. Theclinical use of antibacterial drugs, immunosuppressive agents aer organ transplantation, cancer

chemotherapy, and advances in surgery are associated with increasing risk of fungal infections.Opportunistic pathogens from the genera Candida and Aspergillus as well as pathogenic fungifrom the genus Cryptococcus can invade human organism and may lead to mucosal and skin in-fections or to deep-seated mycoses of almost all inner organs, especially in immunocompromisedpatients. Nowadays, there are some eective antifungal agents, but, unfortunately, some of thepathogenic species show increasing resistance. The identication of fungal virulence factors andrecognition of mechanisms of pathogenesis may lead to development of new ecient antifungaltherapies. This review is focused on major virulence factors of the most common fungal patho-gens of humans: Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. The ad-herence to host cells and tissues, secretion of hydrolytic enzymes, phenotypic switching and mor-phological dimorphism contribute to C. albicans virulence. The ability to grow at 37°C, capsulesynthesis and melanin formation are important virulence factors of C. neoformans. The putativevirulence factors of A. fumigatus include production of pigments, adhesion molecules present on

the cell surface and secretion of hydrolytic enzymes and toxins.

Keywords: pathogenic fungi, virulence factors, aspergillosis, candidiasis, cryptococcosis

INTRODUCTION

In the last decades the problem of severenosocomial fungal diseases has become more seri-ous, especially in patients with severe immunologi-cal impairment. The development of medicine, sur-gery and transplantology in the last thirty years hascaused a dramatic increase in the number of immu-nocompromised individuals who are more suscepti-

ble to fungal infections. Patients with immunologicalimpairment, HIV infection, leukopenia (haematologi-cal malignancy patients), aer surgery, organ trans-

plantation or cancer therapy are at risk of develop-ing mycoses. Widespread use of broad-spectrumantimicrobial agents, immunosuppressive agentsand corticosteroid therapy are also risk factors. Theprophylactic use of antifungal therapies is one of thereasons of frequent resistance to antifungal drugs(Perfect & Casadevall, 2006; d’Enfert & Hube, 2007).Among all the fungi only few species are pathogenicto humans. The most frequently diagnosed fungal

infections are caused by pathogens from the gen-era Candida , Cryptococcus and Aspergillus (Richard-son, 2005). These fungi are ubiquitous and can be

Corresponding author: Justyna Karkowska-Kuleta, Department of Analytical Biochemistry, Faculty of Biochemistry, Bio-physics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland; tel.: (48) 12 664 6544; fax:(48) 12 664 6902; e-mail: [email protected]*Presented at the XXXVI Winter School “Molecule interactions in health and disease” organized by the Faculty of Bio-chemistry, Biophysics and Biotechnology, Jagiellonian University, 21–26 February, 2009, Zakopane, Poland.Abbreviations: ALS, agglutinin-like sequence; GlcNAc, N -acetyl--glucosamine; GPI, glycosylphosphatidylinositol; GXM,glucuronoxylomannan; HBMEC, the human brain microvascular endothelial cells; MAP, mitogen-activated protein; PMN,polymorphonuclear neutrophils; RGD, Arg-Gly-Asp adhesion sequence; SAPs, secreted aspartyl proteinases; SIR2, Silentmating type Information Regulation-2.

Vol. 56 No. 2/2009, 211–224

on-line at: www.actabp.pl


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212 2009 J. Karkowska-Kuleta and others

acquired from host surroundings (Cryptococcus neoformans, Aspergillus fumigatus) or are components ofnormal endogenous ora (Candida albicans) (Perfect& Casadevall, 2006). The mortality among infectedpatients is high, even aer intensive antifungal treat-ment, because of patient’s immunodeciency, latediagnosis or fungal drug resistance. Fungi are ableto cause a disease and to overwhelm the host de-

fense systems because of possessing several genesand proteins associated with their pathogenicity,called virulence factors (Tomee & Kauman, 2000). Many of the putative fungal virulence factors havedeveloped naturally during organism evolution andoriginally acted as a defense against unfavorable en-vironmental conditions, and then, in this way, manyof them became important as virulence factors facili-tating infection.

CANDIDA ALBICANS

Currently more than two hundred ascomyc-etous yeasts are included into the genus Candida , but only a few species are opportunistic pathogensof humans. Nowadays, Candida albicans is thoughtto be the major fungal pathogen of humans. Severe

Candida infections are a serious problem, especiallyin individuals whose immune defense mechanismshave been weakened (Odds et al., 2006). C. albicans can colonize skin and mucosal surfaces of healthypeople and thus occurs commensally in the gastroin-testinal tract, oral cavity and vagina, oen causingsupercial infections (Mavor et al., 2005). Moreover,

C. albicans can enter the bloodstream by direct pen-etration from the epithelium aer tissue damage, or by dissemination from biolms formed on medicaldevices introduced into the patient’s organism, e.g.catheters, dental implants, endoprostheses, articial joints or central nervous system shunts (Chandra etal., 2001; Mavor et al., 2005). Then yeast cells dissem-inate with the blood ow and infect almost all innerorgans, including lungs, kidney, heart, liver, spleenand brain, causing fungaemia and life-threateningsepticaemia. Candidiasis may occur as a result ofdisturbed balance between host immunity and this

opportunistic pathogen. This disorder is not onlydue to the immunological dysfunction of the host, but also to the fungal ability to adapt to new niches,dependent on the expression of infection-associatedgenes (Brown et al., 2007a). These genes and theirproducts contribute to fungal pathogenicity and aredescribed as virulence factors. C. albicans virulencefactors include, among others, production of dier-ent hydrolytic enzymes and adhesins (Chan et al.,1998). There are also other characteristic propertiesthat inuence fungal virulence, for example, the abil-ity to form biolms on various surfaces, to change

morphological form and to switch between variousphenotypes (Chan et al., 1998).

Phenotypic switching

Phenotypic switching is a very important partof fungal adaptability to the changing of environ-ment during invasion of the human organism. The

ability to infect many tissues is crucial to a success-ful aack and dissemination within the host. Occa-sionally some subpopulations of C. albicans cells canchange their morphology, cell surface properties,colony appearance, biochemical properties and me-tabolism to become more virulent and more eectiveduring infection (Odds et al., 2006). Colonies changetheir appearance and assume dierent shapes, in-cluding smooth, rough, fuzzy, wrinkled, fringed orstippled phenotype with a high frequency, approxi-mately one changed colony per 10–104 colonies (Slut-sky et al., 1985). The molecular basis of this process

is still unclear. Probably chromosomal rearrange-ments and a SIR2-like regulation take part in thisprocess (Calderone & Fonzi, 2001). The most popu-lar and well-known example of switched colonies isthe white — opaque switching, when a white, ovaland smooth colony changes into a grey, rough col-ony (Slutsky et al., 1987). The opaque cells produceaspartyl proteinases 1 and 3 and are less virulent,whereas white cells secrete aspartyl proteinase 2 andare more virulent during systemic infection (Yang,2003). Phenotypic switching is most likely a signalof large-scale processes involving changes of manymolecular and biochemical properties of the patho-

gen, which are helpful for fungi to survive withinthe host organism.

Morphological dimorphism

The ability to switch between unicellularyeast cells and lamentous forms called hyphaeand pseudohyphae is known as morphological di-morphism. The transition between these dierentmorphological forms in response to diverse stimuliseems to be very important for fungal pathogenicity(Lo et al., 1997; Chan et al., 1998). The morphology

can change under a variety of environmental condi-tions, including response to physiological tempera-ture of 37°C, pH equal to or higher than 7.0, CO2 concentration of 5.5% or the presence of serum orcarbon sources which stimulate hyphal growth (Eck-ert et al., 2007). The production of unicellular formsis stimulated by lower temperatures and more acidicpH, absence of serum and high concentrations ofglucose (Whiteway & Bachewich, 2006). Yeast cellsare thought to be responsible for dissemination inthe environment and nding new hosts, while hy-phae are required for tissue damage and invasion.

https://www.researchgate.net/publication/12596759_Putative_virulence_factors_of_Aspergillus_fumigatus_Clin_Exp_Allergy?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7394943_Systemic_Fungal_Infections_Caused_by_Candida_Species_Epidemiology_Infection_Process_and_Virulence_Attributes?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7394943_Systemic_Fungal_Infections_Caused_by_Candida_Species_Epidemiology_Infection_Process_and_Virulence_Attributes?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7394943_Systemic_Fungal_Infections_Caused_by_Candida_Species_Epidemiology_Infection_Process_and_Virulence_Attributes?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/6131624_Infection-related_gene_expression_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/6131624_Infection-related_gene_expression_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/6131624_Infection-related_gene_expression_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/51322333_Cell_Wall_and_Secreted_Proteins_ofCandida_albicans_Identification_Function_and_Expression?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/51322333_Cell_Wall_and_Secreted_Proteins_ofCandida_albicans_Identification_Function_and_Expression?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/51322333_Cell_Wall_and_Secreted_Proteins_ofCandida_albicans_Identification_Function_and_Expression?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/19621837_White-opaque_transition_a_second_high-frequency_switching_system_in_Candida_albicans_J_Bacteriol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/19621837_White-opaque_transition_a_second_high-frequency_switching_system_in_Candida_albicans_J_Bacteriol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/19621837_White-opaque_transition_a_second_high-frequency_switching_system_in_Candida_albicans_J_Bacteriol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13922277_Nonfilamentous_C_albicans_Mutants_Are_Avirulent?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13922277_Nonfilamentous_C_albicans_Mutants_Are_Avirulent?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13922277_Nonfilamentous_C_albicans_Mutants_Are_Avirulent?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13922277_Nonfilamentous_C_albicans_Mutants_Are_Avirulent?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13922277_Nonfilamentous_C_albicans_Mutants_Are_Avirulent?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/19621837_White-opaque_transition_a_second_high-frequency_switching_system_in_Candida_albicans_J_Bacteriol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8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Vol. 56 213Virulence factors of pathogenic fungi

Both forms are present in biolms formed on arti-cial substrates (Chandra et al., 2001). Yeast cells havedierent properties than the mycelial forms: the ul-trastructure, biological aributes and composition ofthe cell wall dier between these forms. Probably both forms, yeast cells and hyphae, are necessaryfor full virulence, because mutants lacking genesresponsible for the production of one or the other

are less virulent (Yang, 2003). Despite the fact thatthe production of lamentous form is well knownamong the pathogenic fungi, the molecular basis ofC. albicans morphological dimorphism is still poorlyunderstood. Many genes associated with the forma-tion of dierent cell shape code for transcription fac-tors and may be also responsible for expression ofunknown genes, encoding other virulence factors.Recent studies show that the transcription factorCph1p, whose phosphorylation is regulated througha mitogen-activated protein (MAP) kinase pathwayinvolving products of genes CST20 , HST7 and CEK1,

and the basic helix-loop-helix transcription factorEfg1p are required to form hyphae during infection(Lo et al., 1997). In the Efg1p pathway, the follow-ing proteins are involved: homologs of Ras, adenylcyclase and protein kinase A (TPK2) (Brown & Gow,1999; Lengeler et al., 2000). Other transcription fac-tors, Tup1p and Rbp1p, are negative regulators oflamentation, because mutants lacking these genesexhibit constitutive lamentation (Calderone & Fon-zi, 2001; Yang, 2003). Other putative factors maycontribute to morphogenesis, but their role and exactfunction are so far unknown. It is only obvious thatco-operation of all the signaling pathways involved

in the morphological transition is very important forfungi to infect and survive in the human host.

Adhesion and adhesion molecules

The adherence to the host cells and tissues, aswell as the binding of a set of diverse host proteinsis essential for C. albicans to begin the invasion, fol-lowed by dissemination within the human organ-ism. This step is crucial for fungal survival. On thecell wall surface C. albicans presents receptors whichare responsible for adhesion to epithelial and en-

dothelial cells, serum proteins and extracellular ma-trix proteins (Chan et al., 1998). Adhesion to dif-ferent articial substrates and formation of biolmon medical devices is currently a serious problem inmedicine, because of the frequent resistance to an-tifungal agents and increased pathogenicity amongthe subpopulation of cells forming the biolm. It has been estimated that in the last few decades microbialinfections of humans are strictly correlated with bio-lm formation in 65% of cases (Ramage et al., 2006).C. albicans cells originally present either on the skin,mucosal surfaces or in blood can colonize the sur-

face of medical devices. All known morphologicalforms, yeast cells, pseudohyphae and hyphae, forma biolm and they have dierent properties thanthose of planktonic or suspended cells (Al-Faani &Douglas, 2006). The secretion of aspartyl proteinases(SAPs) is higher during biolm formation (Mendeset al., 2007). C. albicans cells forming a biolm are al-ways associated with a matrix composed of polysac-

charides containing mannose and glucose residues(Chandra et al., 2001). The biolm matrix produc-tion plays a very important role in drug resistanceof C. albicans biolms, but development of resistanceis rather multifactorial (Al-Faani & Douglas, 2006).During biolm formation, C. albicans cells expressseveral genes that inuence pathogenicity. Productsof these genes take part in adhesion (e.g. family ofAls proteins), in carbohydrate synthesis, drug re-sistance (e.g. eux pumps) and in quorum sensing(Chandra et al., 2001).

The ability of Candida to invade dierent en-

vironments in the host organism is a result of greatexibility and adaptability of fungi. This phenome-non is in part due to the presence of dierent adhes-ins connected with cell surface, which facilitate therst stage of infection. These adhesins include Alsproteins family, Hwp1p, Eap1p, Csh1p, and otherless known cell surface receptors. The C. albicans cellwall is constructed from β-glucans (branched poly-mers of glucose residues containing β-1,3 and β-1,6linkages), chitin (unbranched polymers of N -acetyl--glucosamine (GlcNAc) containing β-1,4 bonds),mannoproteins, small amounts of other proteins andlipids (Chan et al., 1998). All known receptors are

tightly connected with the fungal cell wall. The fam-ily of Als proteins (“agglutinin-like sequence”) isone of the well-known examples of Candida adhes-ins. This family includes at least eight ALS genesthat encode proteins with similar structure, whichare connected to the cell surface (Fig. 1). Despitethe fact that members of this family have dierentfunctions and dierent sizes, their structures exhibitsome common properties. In 2004, Sheppard andcoworkers described the structure of the N-terminalfragment of Als proteins. This part contains multi-ple antiparallel β-sheet domains containing minor α-

helical and β-turn components, which indicates thatproducts of ALS genes are members of immunoglob-ulin family (Sheppard et al., 2004). Als1p, Als3p andAls5p are believed to be responsible for adherenceto collagen, bronectin, laminin, endothelial andepithelial cells, Als6p binds to collagen and Als9pto laminin. Als4p probably mediates adherence toendothelium, and Als5p is additionally responsible for cell-to-cell aggregation. The role of Als7p isstill unknown (Filler et al., 2006). A receptor with amolecular mass of approx. 34 kDa, which is presentonly on the surface of hyphal cells, is called Hwp1p

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(Chan et al., 1998). The structure of Hwp1p issimilar to that characteristic for Als proteins, but un-like those, Hwp1p possess in its N-terminal part asequence similar to those of small proline-rich pro-teins of human cells which are substrates for trans-glutaminases present on the surface of epithelialcells. Therefore, Hwp1p facilitates adhesion to epi-thelium (Staab et al., 1999). Another receptor, Eap1p(“enhanced adhesion to polystyrene 1”), shows ho-mology and structural similarity to Hwp1p, butthe host ligands for this protein are still unknown

(Filler et al., 2006). There are also other receptors ofdierent structure, for example Int1p containing anintegrin-like domain and an RGD-binding domain,which bind to dierent extracellular matrix proteinsincluding bronectin, entactin, vitronectin, lamininand collagen, and take part in adhesion to plateletsand endothelial cells (Chan et al., 1998; Calderone& Fonzi, 2001; Ruiz-Herrera et al., 2006). Althoughthe role of alcohol dehydrogenase, Adh1p, in bind-ing of C. albicans cells to bronectin is still unclearthis protein is also thought to have adhesive proper-ties (Filler et al., 2006). Host serum proteins, includ-

ing brinogen (Casanova et al., 1992), plasminogen(Crowe et al., 2003), kininogen (Rapala-Kozik et al.,2008) and others can also be bound by C. albicanscells through dierent receptors, from which someare known and partially characterized. A tighter ad-herence to epithelial and endothelial cells, as well asto extracellular matrix proteins is achieved thanksto increased cell surface hydrophobicity. Singleton

et al. (2001) have described a novel 38-kDa receptor,Csh1p, which enhances hydrophobicity of C. albicans cells, also facilitating specic receptor-ligand interac-tions. Adhesion to host cells is also dependent oninteractions between mannoproteins with lectin-likeproperties and fucosyl or glucosaminyl glycosideson epithelial cells’ surface (Ruiz-Herrera et al., 2006). Although many fungal adhesins have been iden-tied, so far lile is known about the host recep-tors involved in adhesion. At present it is obviousthat Toll-like receptors 2 and 4 and other receptorspresent on the surface of human immune cells, such

as monocytes, macrophages and dendritic cells, areinvolved in these interactions. Probably some pro-teins present on the surface of epithelial or endothe-lial cells, for example N-cadherin, are important for binding of dierent morphological forms of C. albi-cans cells, followed by their endocytosis (Phan et al.,2005; Filler, 2006). Due to the ability to bind and in-vade human endothelial cells C. albicans can traversethe human blood-brain barrier and cause life-threat-ening meningitis (Jong et al., 2001).

Secreted hydrolytic enzymes

Production and secretion of hydrolytic en-zymes, such as proteases, lipases and phospholi-pases are very important virulence factors. Theseenzymes play a role in nutrition but also in tissuedamage, dissemination within the human organism,iron acquisition and overcoming the host immunesystem, and strongly contribute to fungal patho-genicity. Many types of secreted hydrolytic enzymesare currently known for C. albicans. The activity ofphospholipases is very high during tissue invasion, because these enzymes are responsible for hydroly-sis of one or more ester linkages of glycerophos-

pholipids, of which the cell membrane is built. C. al-bicans cells isolated from blood produce higher ex-tracellular phospholipase activities than commensalstrains (Ibrahim et al. , 1995). There are four types ofsecreted phospholipases: A, B, C and D (Calderone& Fonzi, 2001; Yang, 2003), specic towards indi-vidual ester bonds in glycerophospholipids (Ghan-noum, 2000). Very important for fungal virulenceis the activity of phospholipase B (PLB), which has both hydrolase and lysophospholipase-transacylaseactivities (Ghannoum, 2000; Yang, 2003). Thus, PLBcan release fay acids from a phospholipid and the

Figure 1. Scheme of Als adhesin structure.The N-terminal fragment contains a putative signal pep-tide and a ligand-binding domain, central region is rich intandem repeats with many serine and threonine residues,as well as consensus sites for glycosylation. The C-termi-nal part contains a glycosylphosphatidylinositol (GPI) an-chorage site. Aer Filler et al. (2006), modied.

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remaining fay acid from a lysophospholipid, andthen transfer a free fay acid to a lysophospholi-pid and produce phospholipids (Theiss et al. , 2006). Apart from phospholipases, C. albicans can produce atleast nine lipases which can hydrolyze ester bonds ofmono-, di-, and triacylglycerols (Schaller et al., 2005). A well-known group of C. albicans secreted hydro-lytic enzymes are SAPs (secreted aspartyl protein-

ases). The family of SAP genes includes at least tendierent genes SAP1–SAP10 which encode enzymeswith similar functions and character, but dierentmolecular properties, such as molecular mass, iso-electric point and pH for optimal activity (Naglik etal. , 2003). The expression of the SAP genes is regu-lated at the transcriptional level, and the nascentpreproprotein is processed by a signal peptidase inthe endoplasmatic reticulum and by a Kex2-like pro-teinase at the carboxyl-terminal side in the Golgi ap-paratus (Newport & Agabian, 1997; Yang, 2003). Themature enzymes have molecular masses in the range

of 35–48 kDa and two highly conserved regionswith reactive aspartic residues, just as other pepsine-like proteinases (Schaller et al., 2005). Probably SAPs1–3 are secreted only by yeast cells and SAPs 4–6 byhyphal forms (Naglik et al. , 2004; White & Agabian,1995), whereas both forms produce SAPs 9 and 10,which are connected with fungal cell walls becauseof possessing a GPI anchorage site (Hube & Naglik,2001; Albrecht et al. , 2006). The synthesis and func-tion of SAPs 7 and 8 are still under investigation(Yang, 2003). Many host proteins are hydrolyzed by secreted aspartyl proteinases, including colla-gen, laminin, bronectin, mucin, salivary lactofer-

rin, α2-macroglobulin, almost all immunoglobulins,the proinammatory cytokine interleukin-1β, lac-toperoxidase, cathepsin D, complement, cystatine A,and precursors of several blood coagulation factors(Fig. 2) (Naglik et al., 2004; Schaller et al., 2005). Thespectrum of optimal pH for SAPs activity is from2.0 to 7.0, therefore these enzymes may contributeto fungal pathogenesis and developing infections indierent sites in the human organism (Naglik et al.,2004). Except aspartyl proteinases, C. albicans alsosecrets other proteases: a 60-kDa metallopeptidaseand a 50-kDa serine peptidase. The serine peptidase

is active in a broad range of pH (5.0–7.2) and hy-drolyzes many host substrates including extracellu-lar matrix proteins and serum proteins (dos Santoset al., 2006).

Other virulence factors

The ability of pathogenic microorganisms toacquire iron from the environment during infectionis another very important virulence factor. The abil-ity to overcome host systems connected with irontransport and accumulation is crucial for the patho-

gen to survive during invasion of the bloodstream.In C. albicans members of Rbt5 family are needed forutilization of hemoglobin and hemin for iron acquisi-tion by the pathogen. Without these proteins the C.albicans iron metabolism is severely impaired (Weiss-men & Kornitzer, 2004). During infection Candida cells are exposed to reactive oxygen species produced by immune cells, hence the organism expresses sev-eral virulence factors which help to overcome this

host defense mechanism, including catalase, super-oxide dismutase and heat shock proteins (Brown etal., 2007a). Expression of many virulence factors oendepends on environmental conditions, therefore fun-gi must possess a sensor for environmental changes.Probably calcineurin plays the role of such a sensor.Calcineurin is a highly conserved protein involved infungal stress responses, composed of two subunits,the A subunit with catalytic activity and the B subunitwith a regulatory function (Blankenship et al., 2003). The catalytic subunit is encoded by the CMP1 gene(Bader et al., 2003). As a result of calcium inux cal-

modulin binds to calcineurin A subunit, inhibits theaction of the autoinhibitory C-terminal domain of theA subunit, and leads to the formation of the activecalcineurin complex, which has a protein phosphataseactivity. Aerwards calcineurin may inuence the ex-pression of several virulence factors of C. albicans. Inthe case of C. albicans it was shown by Blankenship

et al. (2003) that calcineurin is dispensable for growthat 37°C, germ tube formation, and adherence to thehost cells, but is essential for survival in the humanserum, so fungal pathogenicity strongly correlateswith its activity.

Figure 2. Substrates hydrolyzed by secreted aspartyl pro-teinases (SAPs) during infection.Based on data of Naglik et al. (2003) and Schaller et al.(2005).

https://www.researchgate.net/publication/7023122_Inactivation_of_the_phospholipase_B_gene_PLB5_in_wild_type_Candida_albicans_reduces_cell_associated_phospholiupase_A2_activity_and_attenuates_virulence_Int_J_Med_Microbiol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7023122_Inactivation_of_the_phospholipase_B_gene_PLB5_in_wild_type_Candida_albicans_reduces_cell_associated_phospholiupase_A2_activity_and_attenuates_virulence_Int_J_Med_Microbiol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7023122_Inactivation_of_the_phospholipase_B_gene_PLB5_in_wild_type_Candida_albicans_reduces_cell_associated_phospholiupase_A2_activity_and_attenuates_virulence_Int_J_Med_Microbiol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13868818_KEX2_Influences_Candida_albicans_Proteinase_Secretion_and_Hyphal_Formation?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/8920334_Virulence_factors_of_Candida_species_J_Microbiol_Immunol_Infect?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10717629_Calcineurin_Is_Essential_for_Candida_albicans_Survival_in_Serum_and_Virulence?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10717629_Calcineurin_Is_Essential_for_Candida_albicans_Survival_in_Serum_and_Virulence?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10717629_Calcineurin_Is_Essential_for_Candida_albicans_Survival_in_Serum_and_Virulence?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10601320_Calcineurin_Is_Essential_for_Virulence_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10601320_Calcineurin_Is_Essential_for_Virulence_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10601320_Calcineurin_Is_Essential_for_Virulence_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/13868818_KEX2_Influences_Candida_albicans_Proteinase_Secretion_and_Hyphal_Formation?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7504101_Hydrolytic_enzymes_as_virulence_factors_of_Candida_albicans_Mycoses_48_365-377?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10717629_Calcineurin_Is_Essential_for_Candida_albicans_Survival_in_Serum_and_Virulence?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/8373817_Naglik_J_Albrecht_A_Bader_O_et_alCandida_albicans_proteinases_and_hostpathogen_interactions_Cell_Microbiol_6915-926?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/7023122_Inactivation_of_the_phospholipase_B_gene_PLB5_in_wild_type_Candida_albicans_reduces_cell_associated_phospholiupase_A2_activity_and_attenuates_virulence_Int_J_Med_Microbiol?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/10601320_Calcineurin_Is_Essential_for_Virulence_in_Candida_albicans?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/8920334_Virulence_factors_of_Candida_species_J_Microbiol_Immunol_Infect?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=https://www.researchgate.net/publication/8920334_Virulence_factors_of_Candida_species_J_Microbiol_Immunol_Infect?el=1_x_8&enrichId=rgreq-08e7bbf6-8b86-4ee1-8395-d698f7b045d5&enrichSource=Y292ZXJQYWdlOzI2MzA4MjQ3O0FTOjk5NDU4NDQ4NjI1NjgwQDE0MDA3MjQxNTA3Nzk=


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Tyndall, 1975). A phenoloxidase called laccase isthe crucial cooper-containing enzyme responsiblefor the conversion of diphenolic compounds todopaquinone, followed by their polymerization tomelanin (Williamson, 1994). Laccase is anchored inthe fungal cell wall (Polacheck et al. , 1982). Thereare two paralog genes, CNLAC1 and CNLAC2, en-coding laccase (Zhu & Williamson, 2004). Duringcentral nervous system infection, C. neoformans mayuse neurotransmiers such as dopamine, norepine-phrine and epinephrine as substrates for melanin

production (Casadevall et al., 2000). Some proper-ties of melanin facilitate fungal survival during in-fection. It protects fungi from reactive oxygen spe-cies and plays a role as an antioxidant. It is alsoresponsible for cell wall integrity and negativecharge, and may be important in protection againstantifungal agents and in binding of dierent ions(including iron) to the cell surface. Melanin helps

C. neoformans escape the action of antifungal agentsand to abrogate antibody-mediated phagocytosis(Buchanan & Murphy, 1998; Casadevall et al., 2000;Perfect, 2006).

Mannitol production

Infection of the central nervous system caused by C. neoformans is oen associated with productionof a large amount of the hexitol -mannitol by thisorganism (Liappis et al., 2008). This process mayfacilitate the development of meningoencephalitis, because mannitol increases the osmolality of thesurrounding uid, thus it may contribute to brainedema, and also prevents oxidative damage to thefungus (Wong et al., 1990). Polymorphonuclear neu-trophils (PMN) can kill C. neoformans cells by gen-

erating toxic oxygen metabolites such as OH˙ andHOCl, which are thought to be key eector mol-ecules against C. neoformans , but production of largeamounts of mannitol can protect the fungi fromoxidative killing by PMN or by cell-free oxidants(Chaturvedi et al. , 1996a). Mannitol production isalso thought to be helpful for the pathogen to resistother environmental stresses, since Chaturvedi et al. (1996b) showed that a C. neoformans mutant produc-ing low levels of mannitol was more susceptible toheat stress and osmotic stress. The crucial enzymefor mannitol production by this pathogenic speciesis mannitol dehydrogenase (Perfect et al. , 1996).

Adhesion to host cells and crossing the blood-brain

barrier

When addressing the problem of C. neoformans adhesion to the host cells and proteins it is crucial torecognize all factors which have an inuence on fun-gal pathogenicity, but still the mechanism responsible for adhesion and adhesive structures present onthe fungal cell wall, remain unknown. It was proven by Chang et al. (2004) that cryptococcal infection ofthe central nervous system must be preceded by ad-

hesion to the human brain microvascular endothelialcells (HBMEC), followed by transcellular crossing ofthe blood-brain barrier without disrupting the mon-olayer integrity. Chang and coworkers showed thatthere no C. neoformans cells were present betweenHBMEC, so they excluded the possibility of cross-ing the blood-brain barrier by C. neoformans via aparacellular mechanism. However, Olszewski et al. (2004) suggested that urease production by C. neoformans cells facilitates microcapillaries sequestrationand disruption of endothelial cells and, in conse-quence, crossing the blood-brain barrier via a para-cellular mechanism. Other hypothetical mechanisms

of central nervous system invasion by C. neoformanshave been put forward. Santangelo et al. (2004) andCharlier et al. (2009) postulated that C. neoformans cells could invade the central nervous system bymeans of infected immune cells which could carrythe pathogen within through the blood-brain bar-rier (a “Trojan horse” mechanism). Those authorshypothesized that phagocytosed C. neoformans cellsaer delivery into the brain tissues can escape fromphagocytes and continue invasion and tissue dam-age due to the acidication of the environment andactivation of extracellular phospholipases. C. neofro-

mans has other properties which help in the invasionof the central nervous system. According to Charlier

et al. (2005), the size of C. neoformans cells and themodications of the fungal capsule during centralnervous system invasion suggest the existence of anactive mechanism that may be triggered during oraer crossing of the blood-brain barrier. C. neoform-ans might induce considerable morphological chang-es and actin reorganization aer adhesion to the HB-MEC surface, facilitating engulfment of the fungus by endothelial cells or alteration in tight junctions’permeability (Chen et al., 2003). The mechanism ofcryptococcal invasion of the central nervous system

Figure 3. Cryptococcus neoformans melanogenesis pathway.Aer Buchanan and Murphy (1998), modied.


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is still unknown and requires further investigation,and so are the fungal properties that facilitate cross-ing the blood-brain barrier.


Probably at some stage of infection C. neoformans produces and secretes hydrolytic enzymes,

such as proteases and phospholipases, which playa role in nutrition and tissue damage. Cryptococcalextracellular phospholipase exhibits phospholipaseB (PLB), lysophospholipase (LPL) and lysophos-pholipase-transacylase (LPTA) activities (Chen et al., 2000). The action of this enzyme can result in desta- bilization and destruction of the membranes andlung surfactant, cell lysis and release of lipid secondmessengers (Ghannoum, 2000; Cox et al., 2001). Thephospholipase also enhances the adhesion of C. neoformans cells to the lung epithelium (Ganendren et al.,2006). The activity of the phospholipase is strongly

correlated with cryptococcal virulence, as proved byCox et al. (2001) who constructed plb1 mutants whichwere signicantly less virulent in animal modelsand had a growth defect in a macrophage-like cellline. Probably PLB plays an important role in intra-cellular growth, survival and replication of C. neof-romans within macrophages (Santangelo et al., 2004).One factor which might be involved in the survivalof C. neoformans in the presence of macrophages isthe production of eicosanoids: prostaglandins andleukotrienes, which can down-regulate macrophagefunctions (Noverr et al., 2003). Moreover, the phos-pholipase plays a role not only in the turnover of

cryptococcal cell membrane but also in the mainte-nance of cell wall integrity and therefore fungal sur-vival, particularly during heat stress (Siafakas et al. ,2007). It is also known that C. neoformans possesses aproteolytic activity, but these ndings must be stillinvestigated (Buchanan & Murphy, 1998). Recently,a gene for aspartic proteinase was characterizedand the three-dimensional structure of this proteinwas proposed (Pinti et al., 2007). This protein, calledCnAP1, has two homologous domains, each contain-ing an Asp residue in a conserved position (Pinti etal., 2007). The fungal resistance to reactive oxygen

species is not only due to the mannitol and melaninproduction, but also very important is the produc-tion of Cu, Zn superoxide dismutase, peroxidases,glutathione peroxidase and glutathione reductase,which play a role in resistance to oxidative and nit-rosative species (Brown et al. , 2007b).

C. neoformans can also undergo phenotypicswitching, when parent smooth colonies are changedinto mucoid colonies which are more virulent dur-ing lung infection and can modify the immunologi-cal host response (Guerrero & Fries, 2008). Anothervery important virulence factor of C. neoformans is

its ability to grow in the host’s physiological condi-tions, i.e. at 37°C in an atmosphere of approx. 5%CO2 and a pH higher than 7.0 (Buchanan & Mur-phy, 1998). For the fungal survival in the host organ-ism the presence of an intact gene for calcineurin Ais essential. Calcineurin A is a phosphoserine-phos-phothreonine specic phosphatase encoded by theCNA1 gene (Odom et al., 1997). Aer activation by

pathways connected with fungal stress response cal-cineurin can dephosphorylate specic proteins re-sponsible for pathogenicity and for growth withinthe host organism, but specic targets of this en-zyme need still to be investigated. Disruption of the

CNA1 gene can damage the fungal ability to growat 37°C without aecting the ability to grow at 24°C(Odom et al., 1997).

C. neoformans is also able to acquire iron fromits environment during tissue and bloodstream in-fections. The pathway of signaling of iron presencein the surroundings and iron acquisition is only par-

tially understood. Reductases present at the fungalcell surface can reduce ferric to ferrous iron. Thisprocess is followed by transport of the ferrous ionsinto the cell. This process is mediated by a permease(C1) and ferroxidase (Cfo1) complex connectedwith the plasma membrane (Jung & Kronstad, 2008).The siderophore transporter Sit1, the cell wall pro-tein Cig1 and the mitochondrial proteins Frr1, 3 and4 also play roles in iron delivery and homeostasis.The Cir1 protein controls the transcription of genesencoding those proteins (Jung & Kronstad, 2008).

ASPERGILLUS FUMIGATUS

Aspergillus fumigatus is an ascomycetous,saprophytic and ubiquitous fungus responsible formoulding. It is found worldwide and its small-sizedconidia (2–3 µm) are abundant in the environment(Gniadek & Macura, 2007). Airborne A. fumigatus co-nidia are inhaled by everyone, because their concen-tration in the air is high, approx. 1–100 conidia perm3 (Latgé, 2001). It is also well known that A. fumig-atus conidia are frequently present in food, especial-ly in pepper and tea (Bouakline et al. , 2000), in tap

water (Warris et al. , 2003), at home (Ren et al. , 2001)and in the oce rooms (Buczyńska et al. , 2007). Thismay be the reason why nosocomial acquired infec-tions and community acquired infections quite oendevelop in immunocompromised as well as in im-munocompetent people (Clancy & Nguyen, 1998). Inan immunocompetent person, the ecient immunesystem is usually able to get rid of these conidia, butsometimes even those people may contract invasivepulmonary aspergillosis (Clancy & Nguyen, 1998).However, especially patients with severely impairedimmunity may contract a life-threatening invasive


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pulmonary disease, disseminated infections or cen-tral nervous system infection (Latgé, 2001; Rhodes &Brakhage, 2006). A high mortality rate, from 60% to90%, is correlated with late diagnosis and relative-ly poor knowledge about fungal pathogenicity andvirulence factors (Tekaia & Latgé, 2005; Rementeria

et al. , 2005). There are some features thought to beputative virulence factors, including heat tolerance,

adhesins, pigment production, toxic metabolites andextracellular enzymes, but most of them evolvedas fungal protection against adverse environmentalconditions and their role in pathogenicity is oenunclear (Alp & Arikan, 2008). The functions andcharacter of the putative virulence factors of A. fu-migatus are still under investigation; probably thereis a substantial co-operation between these prop-erties, many of which are regulated by numerousgenes, so it is oen impossible to indicate withoutdoubts which of them contribute to the mechanismof pathogenesis.

Melanin production

A. fumigatus conidia are oen black or greydue to the presence in the cell wall of a pigmentcalled DHN-melanin, which is synthesized fromacetate with participation of enzymatic products ofsix genes (Fig. 4) (Tsai et al. , 1999; Latgé, 2001). Themelanin functions are protection against ultravioletradiation, enzymatic lysis, extreme temperatures, aswell as against reactive oxygen species during infec-tion (Rementeria et al., 2005).

Secreted hydrolytic enzymes

A. fumigatus produces and secretes varioushydrolytic enzymes, including serine and asparticprotease, metalloproteinase, dipeptydylpeptidasesand phospholipases, which contribute to fungal vir-ulence facilitating lung and other tissue colonization.There is a considerable correlation between phos-

pholipase activity and severity of infection (Alp &Arikan, 2008). The serine proteinase and metallopro-teinase have an elastinolytic activity, so lungs beingrich in elastin, the A. fumigatus ability to degrade thisprotein is important during pulmonary infections(Hogan et al., 1996). The serine proteinase (AFA1p)is a member of subtilisin family and can degradenot only elastin but also collagen, brin and brino-

gen. This protein has an extracellular location, but itis also connected with the cell wall (Moutaouakil etal., 1993; Tomee & Kauman, 2000). Apart from thementioned activities, other hydrolytic enzymes areproduced by A. fumigatus , including nucleases andphosphatases (Tomee & Kauman, 2000).

Toxins

Secretion of dierent kinds of toxins to theenvironment or during infection within the humanorganism is one of the characteristic features of A.

fumigatus. The well-known A. fumigatus toxin aa-toxin, which has hepatotoxic and carcinogenic fea-tures probably is not produced in the human or-ganism during infection, because its expression isregulated by many genes under complex inuenceof environmental conditions (OBrian et al., 2003;Rementeria et al., 2005). The most important toxinwith a well-proven in vivo activity is gliotoxin. Thissecondary metabolite from the epipolythiodioxopi-perazine family has immunosuppressive properties, because it can inhibit macrophage phagocytosis,T-cell activation and proliferation, and can inducemacrophage apoptosis (Hogan et al., 1996). Gliotoxin

is also responsible for slowing ciliary beating in therespiratory tract and for epithelial layer damage, sothe fungal cells cannot be eciently removed fromthe host organism (Tomee & Kauman, 2000). An-other toxin secreted in vivo is resticotocin, an 18-kDa protein (Aspf1) which cleaves a phosphodiester bond in 28S rRNA of eukaryotic ribosomes (Lamy etal., 1991; Hogan et al., 1996). A. fumigatus also pro-

Figure 4. Pathway for melanin synthesis by Aspergillus fumigatus.Aer Latgé (2001), modied.


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duces other immunosuppressive toxins, for examplethe 14-kDa conidial inhibitory factor and AfD, A. fu-migatus diusible product. Pyrogenic, cytotoxic andshock-evoking activities are also characteristic forother endotoxins produced by A. fumigatus , includ-ing fumitremorgins, fumagilin, fumagatin and hel-volic acid (Tomee & Kauman, 2000).


The molecular basis of A. fumigatus patho-genicity is associated with its ability to adhere tohost tissues and with binding to dierent host pro-teins, including laminin, brinogen, surfactant Aand D, complement, immunoglobulin and bronec-tin through dierent receptors connected with thefungal cell wall, which is built of α, β-1,3-glucan,galactomannan and chitin (Latgé, 2001). The ga-lactomannan can be used as a diagnostic factor, because during infection it can be found in the se-

rum, urine and cerebrospinal uid (Latgé, 1999; Re-menteria et al., 2005). Probably laminin and brino-gen have a common receptor or distinct receptors, but tightly packed on the surface of conidia (Tomee& Kauman, 2000). A. fumigatus conidia are cov-ered with a layer of hydrophobic proteins, called“rodlet layer” built from proteins encoded by atleast two genes, RODA and RODB, responsible foradhesion to albumin and collagen (Latgé, 2001).Protection against reactive oxygen species pro-duced by human immune cells during inamma-tory state is also important for developing a fungalinfection, therefore A. fumigatus has an ability to

produce catalases and superoxide dismutases (Lat-gé, 2001). Three catalases are expressed by A. fumigatus. CatA, a homodimeric enzyme composed oftwo 84.5-kDa subunits, is connected with conidia.The other two catalases, Cat1p and Cat2p, are con-nected with hyphae and have dierent structures, because the rst one is composed of four 90-kDasubunits, and the second is a monomer. Despitethe fact that these enzymes can protect A. fumigatus against reactive oxygen species in the environmenttheir role as virulence factors during infection isnot clear (Paris et al., 2003). Perhaps there are other

enzymes with such activity which contribute to thefungal pathogenicity. It has also been proven that A. fumigatus superoxide dismutases, containing Mnor Cu and Zn, can eciently prevent the fungusfrom oxidative damage (Rementeria et al., 2005).The optimal temperature for A. fumigatus growthis 37°C, but it is able to grow even at 55°C and tosurvive temperatures near 75°C (Tekaia & Latgé,2005). There are some indications that calcineurincatalytic A subunit, encoded by the CNAA gene, isvery important for A. fumigatus growth, tissue in-vasion and pathogenicity (Steinbach et al., 2006).

CONCLUSIONS

The recent progress in medical techniques,transplantology and antimicrobial treatment is un-fortunately the reason of the increasing frequencyof invasive fungal infections and high mortalityrate, even 90%, among patients with disseminatedcandidiasis, aspergillosis or cryptococcosis (Rich-

ardson, 2005). Additionally, the diagnosis is oendicult because of non-specic symptoms andproblems in isolation and identication of fungi(Hinrikson et al. , 2005). At present, the majority ofpathogenic fungi are susceptible to conventionalantifungal treatment, but an increasing resistanceto some antifungal drugs is a new, important prob-lem in medicine. Currently used antifungal drugs belong to one of four groups of dierent characterand mechanism of action (Sanglard & White, 2006).The rst group, the polyenes represented by am-photericin B, target ergosterol, a sterol present in

the fungal cell membrane, and make pores caus-ing cell death (White et al., 1998). Amphotericin Bmay be used for treating infections caused by C.albicans , C. neoformans and A. fumigatus. The mainproblem with polyene therapy is that at high andecient concentrations they are nephrotoxic andmust be injected intravenously because of poor sol-ubility (Sanglard & White, 2006).The second groupof antifungal drugs is ergosterol biosynthesis in-hibitors, which include azoles, morpholines and al-lylamines. They can inhibit the late pathway of er-gosterol biosynthesis and cell division, causing lossof membrane structure and function (White et al. ,

1998). Azoles are the most popular drugs from thisgroup, and they can be divided into two classes:imidazoles, which include ketoconazole and clot-rimazole used for supercial infections, and tria-zoles, which include uconazole, voriconazole anditraconazole used for systemic infections (Sanglard& White, 2006). Azoles are used for treating can-didiasis, but voriconazole is also important for as-pergillosis therapy (Macura et al. , 2000; Pawlik etal. , 2006), whereas uconazole is used for crypto-coccosis therapy because of its ability to cross the blood-brain barrier (Sanglard & White, 2006). The

third group includes inhibitors of nucleic acid syn-thesis, i.e. 5-ucytosine (Sanglard & White, 2006).The fourth, the newest category of antifungaldrugs, includes echinocandins which target glucansynthase. One echinocandin, caspofungin, is cur-rently used for treatment of Candida and Aspergillusinfections; other echinocandins, anidulafungin andmicafungin, are in clinical trials (Sanglard & White,2006). A serious problem in treatment of fungal in-fections is the resistance to azoles and 5-ucytosinethrough a mechanism dependent on alternations inthe target enzyme and in drug eux pumps (Es -


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pinel-Ingro, 2008). A way to avoid developingresistance is to use multidrug therapy or dierentantifungal agents, as well as to limit too frequentand uncontrolled usage of the newest category ofdrugs (Sanglard & White, 2006). It is also necessaryto recognize the mechanism of pathogen–host in-teractions at the molecular level in order either toprevent the infection or to develop new strategies

for therapy and new eective antifungal drugs. Al-though the knowledge of the fungal pathogenicityand molecular basis of their virulence is alreadysignicant, this issue needs further investigation.

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