A fumigatus Virulence Factors Overview

There are two opposing views of A. fumigatus virulence in IA. The 'fungal-centric' approach argues that the virulence of A. fumigatus is a result of specific fungal virulence factors. It advocates identifying a lengthy list of A. fumigatus virulence factors that contribute to its ability to invade the host and cause disease. According to this approach, only by carefully dissecting these factors, alone and in combination, can we begin to understand the molecular basis for the various infections caused by A. fumigatus. In contrast, the 'immuno-centric' approach argues that A. fumigatus virulence results from the immunosuppression or genetic deficiency of the host rather than from specific and unique fungal determinants. According to this approach the fungus infects the host not because it has developed unique systems but because the colonized host exhibits very weak defense immunity. It is a pathogen only because of very simple biological reasons: it is a hardy and ubiquitous generalist, and all humans come into daily contact with it. The approach taken in this chapter is that these two 'world-views' are complementary: in Aspergillus infections there is a complex interplay between pathogen virulence factors and the host immune system. These two sides of the coin will be described and integrated in the following sections.

Virulence factors: a definition. Virulence factors are defined as pathogen determinants that cause damage to the infected host (Casadevall, 2005). Damage caused by the pathogen is either direct or indirect. Direct damage can be offensive (i.e. by secreted enzymes, toxins, adhesins), or defensive (thermotolerance, melanin, hydrophobins, ROS detoxifying enzymes, efflux pumps, etc.). Indirect damage is caused by the host response (necrosis, inflammation) to specific pathogenic determinants (i.e. antige ns). This definition naturally excludes fungal genes encoding key biosynthetic proteins such as PABA synthase (Brown et al., 2000) and orotidine-5'-phosphate decarboxylase (D'enfert, 1996). An additional constraint is that deletion of the gene encoding a virulence factor reduces virulence without affecting normal in vitro growth.

A. fumigatus virulence factors were developed for life in decaying vegetation. A central assertion of this review is that the virulence factors of A. fumigatus were not developed to infect humans. Rather, they are abilities that enable it to survive and compete in the soil environment. When the fungus accidentally infects humans, it fortuitously uses some of these natural capabilities to survive. For example, to poison its competitors in the soil A. fumigatus has become adept at chemical warfare: it contains 26 clusters of genes controlling the production of secondary metabolites, primarily toxic molecules. To facilitate efflux of toxic compounds secreted by competing soil microorganisms, its genome contains over 40 ABC cassette transporters and 100 major facilitator transporters, far more than in yeast (Nierman et al., 2005). These genes may enable it to poison and weaken its human host, and resist the action of drugs and chemicals. Additional virulence factors, such as the presence of a tough melanized conidial cell wall highly resistant to degradative enzymes and oxidative stress, may have developed to enable A. f umigatus to survive being consumed by organisms such as soil amoeba and nematodes. Such factors may coincidentally protect it from macrophages that use similar mechanisms to dispose of pathogens (Fuchs & Mylonakis, 2005).

A. fumigatus virulence is multifactorial. In A. fumigatus multiple survival traits contribute towards virulence. For example, A. fumigatus is neither unique among the filamentous fungi in possessing a large number of efflux pumps or genes for producing secondary metabolites, nor is it more commonly found in human surroundings (Hospenthal et al., 1998; Shelton et al., 2002). Yet it is the most common human mold pathogen. One possible explanation is that A. fumigatus possesses a unique combination of different traits that together make it the primary mold pathogen in the world. For example, none of the other, less pathogenic Aspergilli or other common airborne fungi such as Alternaria, Penicillium, and Cladosporum species may have the multifactorial combination of small conidial size, resistance to oxidants and thermotolerance in one package.

Different virulence factors for different diseases. Because A. fumigatus is capable of causing a wide range of diseases depending on the immune system of the host, it is quite obvious that those A. fumigatus virulence factors causing allergic aspergillosis will differ considerably from those involved in invasive aspergillosis. In the former, we can expect to find such factors as immunogenic surface and secreted proteins and the ability to withstand a strong immune response, whereas in the latter, crucial factors may be the ability to withstand acidic necrotic surroundings, and overcome the lack of specific vital nutrients and elevated body temperatures found in the infected immunocompromised host.

A. fumigatus virulence factors are found in large, often redundant gene families. Complicating matters further, many of the suspected A. fumigatus virulence factors are found in large, often redundant gene families. Their analysis presents a formidable technical challenge. For example, the A. fumigatus genome encodes for at least 38 different secreted proteases, five catalases, and six lysophospholipases (see below) and all are suspected virulence factors. To conclusively establish the importance of these gene families in A. fumigatus virulence, it will be necessary to delete all the known members in a single mutant strain. This is technically problematic: A. fumigatus lacks a sexual life cycle and therefore repeated rounds of transformation are required to delete each gene in turn, using a limited available number of dominant selectable markers. Because the process of transformation is inherently mutagenic, repeated rounds of transformation greatly increases the risk of introducing secondary nonspecific mutations in the final strain. Possible technical solutions to this problem may include the use of RNAi designed to hybridize with a conserved family sequence (although gene repression is never total and the RNAi plasmid is unstable over time) (Mouyna et al., 2004; Mouyna et al., 2006, in press) or the deletion of family-specific transcription factors (Bok & Keller, 2004).

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