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The kingdom of fungi consists of a number of species that are associated with a wide spectrum of diseases in humans and animals, ranging from allergy and autoimmunity to life-threatening infections. Most fungi (such as Histoplasma capsulatum, Paracoccidioides brasiliensis, Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neoformans, Aspergillus fumigatus , and Pneumocystis jirovecii ) are ubiquitous in the environment. Some, including Candida albicans , establish lifelong commensalism on human body surfaces. Not surprisingly, therefore, human beings are constantly exposed to fungi, primarily through inhalation or traumatic implantation of fungal elements. The most common of the human diseases caused by fungi are the opportunistic fungal infections that occur in patients with defective immunity. This chapter is an advanced attempt to analyze the role of innate and adaptive immunity in resistance to pathogenic fungi. Through the involvement of different pattern recognition receptors, cells of the innate immune system not only discriminate between the different forms of fungi, but also contribute to discrimination between self and pathogens at the level of the adaptive T helper (Th) immunity (Romani, 2004b and references therein). Thus, the traditional dichotomy between the functions of innate and adaptive immunity in response to fungi has been recently challenged by the concept of an integrated immune response to fungi (Romani, 2004b and references therein).

According to the molecular Koch’s postulates (Falkow, 1988), putative virulence traits can be identified in a pathogen because deletion of the gene encoding a virulence factor in an otherwise wild-type strain generates a mutant with reduced pathogenicity in a certain model of experimental infection. This chapter reviews the main in vitro models for epithelial, endothelial, and immune system cells. It outlines the available techniques to characterize and to quantify host cell-pathogen interactions following a structure as preset by the pathogenic course itself. Examples on how the in vitro methodology has contributed to clarify the effective molecular mechanism in the single steps are included for the different fungal pathogens.

Insects represent one of the most successful groups of animals, exploiting almost all niches on Earth, except the seas, and accounting for at least 1 million species and 10 individuals (Vilmos & Kurucz, 1998). Insects diverged from vertebrates approximately 500 million years ago and despite this early divergence, have maintained an immune response with strong structural and functional similarities to the innate immune response of mammals (Vilmos & Kurucz, 1998; Salzet, 2001). Insects rely exclusively upon an immune system analogous to the innate immune response of mammals and consequently have become extremely valuable as models for studying vertebrate innate immune responses to many pathogenic micro-organsims. There are obvious ethical concerns with using mammalian models for in vivo testing of microbial pathogens, many of which can be removed by employing invertebrate models. Invertebrates, such as insects, do not have a well-developed nervous system and consequently do not experience pain in the same manner as mammals. Although invertebrate models would not be the only source of in vivo testing, they have the potential to substantially reduce the number of mammals sacrificed. In addition using invertebrates as models to study the pathogenicity of microbes yields faster results.

Advances in cancer medicine, transplantation biology, management of AIDS patients, and diabetics are responsible for the alarming expansion rates in the number of immunocompromised patients susceptible to life-threatening fungal infections. In response to these concerns, researchers have successfully labored at modifying some of the existing antifungals (polyenes and azoles) and introducing novel therapies (peptides, oligonucleotides, and monoclonal antibodies (MAbs)) that have collectively expanded the spectrum of activity and minimized associated side effects. Nonetheless, the classical approach of dealing with fungal infections by targeting the pathogen remains prone to failure over time owing to the extensive genetic flexibility of fungi to evade or resist antifungal therapeutics. Conditioning or modulating the immune system of the host may help circumvent the resistance problem. Vaccines, cytokines, and adoptive T cell transfer are the backbone of this approach.

Candida albicans is commonly found in the gastrointestinal tract, oral cavity, and genital area as a harmless commensal. Based on recent studies in healthy individuals, asymptomatic oral carriage of Candida species is estimated to occur in 24–70% of children and adults, with a reduced frequency in babies less than 1 year of age (Table 5.1). Of isolates identified, the majority are C. albicans (38–76% in adults and children). Again, the frequency of C. albicans differs across different age groups, with a far greater proportion of isolates identified as C. albicans in young babies and in the elderly (Table 5.1). Higher oral carriage rates are found in HIV positive patients (Sanchez-Vargas et al., 2005a; Liu et al., 2006) and diabetics (Belazi et al., 2005).

Cryptococcus neoformans ( Cn ) is a fungal pathogen, commonly found in urban environments (Tampieri, 2006) that primarily affects immunocompromised individuals through inhalation of spores. In healthy individuals Cn infection is usually cleared, or can remain in a latent form for prolonged periods of time. However, in individuals with impaired immune function, the infection may spread to the central nervous system (CNS), causing life-threatening meningitis (Casadevall & Perfect, 1998; Hull & Heitman, 2002). Thus, the disease is relatively common in AIDS patients. A recent study shows that the prevalence of cryptococcosis has declined with the increasing availability of highly active retroviral therapy (HAART) to treat HIV (Lortholary et al., 2006; Mirza et al., 2003). However, the disease continues to be a problem for those with limited access to HAART, especially in the developing world (Banerjee et al., 2001; Marques et al., 2000). Another group of individuals who are susceptible to cryptococcosis are organ transplant recipients receiving immunosuppressive therapy (Husain et al., 2001; Vilchez et al., 2002). However, cryptococcosis is not limited to immunocompromised persons, as shown by the recent outbreak in Vancouver among healthy individuals (Hoang et al., 2004).

The class Zygomycetes is a large group of fungi that comprise two orders of medical interest, the Mucorales and the Entomophthorales. Zygomycoses caused by Entomophthorales are generally chronic infections seen in immunocompetent patients, mostly in tropical areas (Dromer & McGinnis, 2002). General description of Entomophthorales and associated diseases have been reviewed recently (Prabhu & Patel, 2004; Ribes et al., 2000) and as no major advancement has been made recently in the knowledge and management of entomophthoromycosis, these fungi will not be detailed in this chapter. Human pathogens belonging to the order Mucorales are grouped into six families (Table 7.1) and comprise approximately 20 species in approximately 10 genera. The most frequent species responsible for zygomycosis are Rhizopus spp., Mucor spp., Rhizomucor spp., and Absidia spp. (Ribes et al., 2000). Other species such as Cunninghamella bertholletiae, Apophysomyces elegans , and Saksaenea vasiformis have been less frequently reported as etiological agents of zygomycosis.

The aim of this chapter is to analyze Aspergillus fumigatus virulence in light of recent developments in genomics and our growing understanding of the complexity of the host–pathogen interaction. Readers interested in comprehensive summaries describing putative virulence determinants of A. fumigatus are directed to several excellent recent reviews (Latge, 1999; Rementeria et al., 2005; Brakhage, 2005).

Fungal pathogens are a significant public health problem, being responsible for a large and growing percentage of deaths from hospital-acquired infections (Asmundsdottir et al., 2002; Chakrabarti & Shivaprakash, 2005; McNeil, et al., 2001). A group of these pathogens are dimorphic, alternating between two different growth forms (Gow, 1995). The yeast form is unicellular, generally spherical, ellipsoid, or cylindrical in shape, and uninucleate due to coupled mitosis and cytokinesis (Figure 9.1). The filamentous form consists of highly polarized fibrillar cells, which elongate by apical growth, placing crosswalls called septa at regular intervals, exhibit incomplete cell separation, have the capacity to generate new grow foci by branching and are generally multinucleate. The ability to alternate between the yeast and filamentous growth forms is a tightly regulated process known as dimorphic switching. The different growth forms represent cell types with different physiological properties, which are adapted to their respective environments. Interestingly, for most pathogenic dimorphic fungi only one growth form predominates during infection. Therefore, dimorphic switching is an intrinsic property of pathogenicity (Berman & Sudbery, 2002; Andrianopoulos, 2002; Lengeler et al., 2000).

Dermatophytes are exogenous pathogens that cause common superficial infections of the skin and keratinized structures arising from it, such as the hair and nails, known as tinea or dermatophytosis. While there are some fungi such as the lipophilic yeasts or Malassezia species that are part of the normal flora of the skin, dermatophytes are acquired from an external source. Dermatophytes are mould fungi which evolved from soil dwelling organisms, the keratinophilic fungi, that adapted to live in an environment where there was shed hair or skin, e.g. in the vicinity of animal homes or burrows. They adapted to invade keratin on living hosts and to cause infections on animals or humans. Dermatophytes are therefore known as geophilic, zoophilic, or anthropophilic depending on whether they originate from soil, animals, or humans, respectively.