Two modes of acquisition of Fusarium spp. seem likely: (i) respiratory, following inhalation of conidia and (ii) cutaneous (via trauma, burns, catheters, or other foreign bodies), as in cases of cellulitis, catheter-related infections, and burns. The predominant mode of infection is inhalation of conidia into the respiratory system and establishment in the lungs. It is well known that host defence mechanisms [especially macrophages, neutrophils, and monocytes (MNCs)] influence the manifestation and severity of fungal infections; thus, clinical forms of the disease depend on a patient's immune response. If the host is unable to effectively clear the primary pulmonary infection, widespread hematogenous dissemination may occur. In addition, Fusarium spp. possess several cellular and molecular attributes that may confer different degrees of inherent virulence on these organisms. The combination of these virulence factors and the immunocompromised status of the host contribute to the development of invasive fusarial infections. Risk factors for disseminated fusariosis include severe immunosuppression (mainly patients with haematological malignancies) in addition to colonization and tissue damage. Specifically, conditions like neutropenia, lymphopenia, corticosteroid therapy or any other immunosuppressive treatment, graft versus host disease, receipt of a graft from an HLA mismatched or unrelated donor are considered risk factors for disseminated fusariosis (Guarro & Gene, 1995; Marr et al., 2002; Raad et al., 2002).

Fusarium spp. possess several virulence factors including the production of fumonisins, fusarins, moniliformin, and other mycotoxins. These factors can cause mycotoxicoses in humans due to suppression of humoral and cellular immunity. In addition, Fusarium spp. have the ability to produce proteases and collagenases, and also to adhere to prosthetic material such as catheters and contact lenses making biofilms (Dignani & Anaissie, 2004).

Release of toxins, enzyme production, and adherence to prosthetic materials, have all been postulated as virulence factors for Fusarium spp. infection. Specifically, mycotoxins produced by Fusarium spp. such as trichothecenes, deoxynivalenol (vomitoxin), and fumonisin affect the immune system by decreasing proliferation and function of lymphocytes, protein synthesis, and phagocytosis by macrophages and chemotaxis of neutrophils (Forsell et al., 1986; Nelson et al., 1994). In addition, these mycotoxins decrease the number of lymphocytes and MNCs, the levels of immunoglobulin M and immunoglobulin A and finally the phagocytic function of macrophages (Visconti et al., 1991; Qureshi & Hagler, 1992). Several mycotoxins induce leukopenia and marrow destruction and suppress platelet aggregation. Definitive evidence linking enzyme production to the virulence of Fusarium spp. is lacking. In vitro production of proteases by F solani and of collagenases by F. moniliforme has been documented. However, whether these enzymes play a role in the pathogenesis of human fusariosis remains to be determined.

Polymorphism in the trichothecene mycotoxin gene cluster of Fusarium spp. has been found in phytopathogenic Fusarium spp. Phylogenetic analyses have demonstrated that polymorphism within these virulence-associated genes is specific and appears to have been maintained by balancing selection acting on chemotype differences that originated in the ancestor of Fusarium spp. In addition, chemotype-specific differences, evidence of adaptive evolution within trichothecene genes, have also been reported (Ward et al., 2002). Although data on polymorphism of human pathogenic Fusarium spp. are very limited, in an analysis of 33 F oxysporum complex isolates coming from patients of the same US hospital, it was found that a recently dispersed, geographically widespread clonal lineage was responsible for over 70% of all clinical isolates investigated. Moreover, strains of the clonal lineage were conclusively shown to genetically match those isolated from the hospital water systems of three US hospitals, providing support for the hypothesis that hospitals may serve as a reservoir for nosocomial fusarial infections (O'Donnell et al., 2004).

The mode of Scedosporium spp. invasion and subsequent propagation to the host remains ambiguous. Clinical experience suggests the respiratory tract as the most probable portal of entry of Scedosporium spp. infection (Steinbach & Perfect, 2003). Consistently, lungs appear to be the most frequent sites of S. apiospermum infections (Salesa et al., 1993). However, spores may infect a patient through the gastrointestinal tract from ulcerative lesions or by direct inoculation from areas with trauma or a central venous catheter and eventually disseminate to multiple organs including brain, kidney or heart (Berenguer et al., 1997). Additionally, angiotropism and perineural invasion with subsequent dissemination along the nerve sheet may represent another means of spread of the disease as it has been suggested for other filamentous fungi (Frater et al., 2001).

Although the pathogenic mechanisms and virulence factors of Scedosporium spp. infection have not been fully elucidated, recent studies have described the role of different pathogenic determinants. Generally, S. prolificans isolates show comprehensive in vitro and in vivo resistance to currently used antifungals and therefore they are considered more virulent than S. apiospermum isolates (Hennequin et al., 1997; Ortoneda et al., 2002b; Carrillo & Guarro, 2001). One possible explanation of S. pmlificans drug resistance is the presence of melanin (Ruiz-Diez & Martinez-Suarez, 2003). Melanins are dark brown or black pigments of high molecular weight formed by oxidative polymerization of phenolic compounds. Most fungal melanins are derived from the precursor molecule 1,8-dihydroxynaphthalene (DHN) through the polyketide biosynthetic pathway and reside in ascomycetes and related deuteromycetes (Jacobson, 2000). There are several hypotheses supporting the protective role of melanin against host defense mechanisms and environmental stress. A growing body of evidence supports melanin's function as antioxidant. Melanin may have a protective effect on the fungus by scavenging oxygen and nitrogen free radicals, produced by phagocytic cells during oxidative burst. Additional melanin pathogenetic mechanisms include sequestration of host defensive proteins, cross-linking or shielding cell wall constituents against hydrolytic enzymes, or conferring resistance to heat (Jacobson et al., 1995; Schnitzler et al., 1999). The role of melanin in virulence as protection for the pathogen against immunologically generated free radicals has been modelled on Cryptococcus neoformans. It has been shown that melanized cells survived approximately tenfold better than did non-melanized cells (Wang & Casadevall, 1994). Further studies have not demonstrated any apparent difference in terms of MIC of various antifungal agents, between the melanin-lacking mutants and the wild-type isolates of S. prolificans (Ruiz-Diez & Martinez-Suarez, 2003).

Larcher et al. have isolated and characterized a serine proteinase of the subtilisin family that is secreted by S. apiospermum (Larcher et al., 1996). From studies performed on cystic fibrosis patients it is known that proteinases, secreted by fungal pathogens like A. fumigatus or S. apiospermum contribute to pulmonary damage by degrading host proteins like fibrinogen and basement membrane laminin or indirectly by hypersensitivity mechanisms (Lake et al., 1990; Tronchin et al., 1993; Miller et al., 1993). Consequently, there is presumptive evidence, that serine proteinase from S. apiospermum may act like the alkaline proteinase of A. fumigatus by degrading human fibrinogen mediating, in this way, to the severe bronchopulomonary inflammation of the cystic fibrosis patients. In this regard, proteinase inhibitors may constitute an attractive future therapeutic alternative aiming to control the inflammation response (Larcher et al., 1996).

The predilection of Scedosporium spp. to CNS dissemination may be explained by the siderophore activity of these fungal strains (Panackal & Marr, 2004). Further biochemical and genetic studies are needed in order to determine the pathogenetic potential of Scedosporium spp.

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