Abstract
Fonsecaea pedrosoi is a dematiaceous fungus and the main causative agent of chromoblastomycosis that is a chronic disease usually affecting the human skin and subcutaneous tissues, which causes deformations and incapacities, being frequently refractory to available therapies. A typical globe-shaped, multiseptated and pigmented cells, known as sclerotic cells, are found in the lesions of infected individuals. In the present work, we have investigated the production of aspartic-type peptidase in F. pedrosoi sclerotic cells as well as the effect of peptidase inhibitors (PIs) on its enzymatic activity and viability. Our data showed that sclerotic cells are able to secrete pepstatin A-sensible aspartic peptidase when grown under chemically defined conditions. In addition, aspartic PIs (ritonavir, nelfinavir, indinavir, and saquinavir), which are clinically used in the HIV chemotherapy, significantly decreased the fungal peptidase activity, varying from 55 to 99%. Moreover, sclerotic cell-derived aspartic peptidase hydrolyzed human albumin, an important serum protein, as well as laminin, an extracellular matrix component, but not immunoglobulin G and fibronectin. It is well-known that aspartic peptidases play important physiological roles in fungal cells. With this task in mind, the effect of pepstatin A, a classical aspartic peptidase inhibitor, on the F. pedrosoi proliferation was evaluated. Pepstatin A inhibited the fungal viability in both cellular density- and drug-concentration manners. Moreover, HIV-PIs at 10 μM powerfully inhibited the viability (>65%) of F. pedrosoi sclerotic cells. The detection of aspartic peptidase produced by sclerotic cells, the parasitic form of F. pedrosoi, may contribute to reveal new virulence markers and potential targets for chromoblastomycosis therapy.
Highlights
Fonsecaea pedrosoi is a melanized saprophytic filamentous fungus able to cause a chronic, progressive and granulomatous skin and/or subcutaneous tissue infections, named chromoblastomycosis, which occur most frequently in humid tropical and subtropical regions of America, Asia and Africa (Santos et al, 2007; Queiroz-Telles et al, 2017)
We have shown that chromoblastomycosis fungi secrete distinct peptidases and that these enzymatic profiles are closely related with fungal morphology and cultivation conditions (Palmeira et al, 2006a,b, 2008, 2017; Granato et al, 2015)
After the growth of F. pedrosoi sclerotic cells under chemically defined conditions (Figure 1A), the culture supernatant was incubated with soluble bovine serum albumin (BSA), at different pHs, in order to evidence its possible cleavage by any released fungal peptidase (Figure 1B)
Summary
Fonsecaea pedrosoi is a melanized saprophytic filamentous fungus able to cause a chronic, progressive and granulomatous skin and/or subcutaneous tissue infections, named chromoblastomycosis, which occur most frequently in humid tropical and subtropical regions of America, Asia and Africa (Santos et al, 2007; Queiroz-Telles et al, 2017). This dimorphic fungus produce different morphotypes including conidia (reproduction structures) and mycelia (filamentous forms), both are usually found in its saprophytic lifestyle, as well as sclerotic cells (synonymous with muriform or medlar bodies), which are the parasitic forms observed in the infected tissues (Rippon, 1988). The cellular morphology, ultrastructure, as well as the antigenic cross-reactivity between in vivo and in vitro sclerotic cells confirmed their similarity, showing that the latter can be used in experiments aiming to understand the physiopathology of chromoblastomycosis fungi (Silva et al, 2002)
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