Introduction

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.

Recent advances in molecular genetics have led to the generation of such altered strains in several clinically relevant fungi, including Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Histoplasma capsulatum. This has, in turn allowed the identification of several virulence genes involved in important physiological processes in the pathogen. These processes include, among others, the biogenesis of the cell wall, the acquisition of nutrients, the production of extracellular enzymes, and the tolerance to stress. In experimental infection models these mutants frequently display attenuated or abolished virulence. While this methodology provides global information on whether a gene is involved in virulence or not, it does not define the specific step(s) in the pathogenic process that is (are) impaired by the molecular lesion.

During the pathoenic cycle fungi interact with various types of host cells, which may lead to dissemination from the original entry site and deep-seated infection of inner organs (Figure 2.1).

This interaction is characterized by successive events at the cellular level. Fungi first attach and then enter the host cells, where they may persist or even proliferate before they leave and infect other host cells and tissues. Each of these steps may be crucial for the development of the disease, and virulence factors may contribute in each of these steps by different molecular mechanisms (Figure 2.2). In vitro models of infection provide a defined experimental set-up to characterize the host-pathogen interplay at a cellular level and allow us to ascertain more precisely the molecular lesion present in the mutant and the corresponding step of the pathogenic process specifically altered.

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

K. Kavanagh (ed.), New Insights in Medical Mycology. © Springer 2007

Figure 2.1 Stations of the pathogenic cycle. Fungi can enter the body interior through various epithelial sites which mark the boundary between inside and outside (1). The host's defence either limits the interaction to the epithelial surface or the fungus overcomes the barrier. The infection becomes invasive and no longer restricted to the primary infection site. A key feature initiating dissemination (2) is the interaction of the pathogen with host cells of the blood system - endothelial or immune cells. The fungus can get access to the bloodstream by transcellular (a), paracel-lular (b), or 'Trojan horse' (c) mechanisms by which it might also leave the vascular system to attack finally vital organs as the brain, the liver, or the kidneys (3)

Figure 2.1 Stations of the pathogenic cycle. Fungi can enter the body interior through various epithelial sites which mark the boundary between inside and outside (1). The host's defence either limits the interaction to the epithelial surface or the fungus overcomes the barrier. The infection becomes invasive and no longer restricted to the primary infection site. A key feature initiating dissemination (2) is the interaction of the pathogen with host cells of the blood system - endothelial or immune cells. The fungus can get access to the bloodstream by transcellular (a), paracel-lular (b), or 'Trojan horse' (c) mechanisms by which it might also leave the vascular system to attack finally vital organs as the brain, the liver, or the kidneys (3)

pathogenic course itself (Figure 2.2). 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.

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