DNA-hsp65 Vaccine as Therapeutic Strategy to Treat Experimental Chromoblastomycosis Caused by Fonsecaea Pedrosoi

Abstract

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. Patients with the disease are still considered a therapeutic challenge, mainly due to its recalcitrant nature. There is no "gold standard" treatment for this neglected mycosis, but rather there are several treatment options. Chemotherapy alternatives include 5-flucytosine, itraconazole, terbinafine, fluconazole, thiabendazole, ketoconazole and amphotericin B, although the healing of severe cases is still uncommon. However, several studies have reported the DNA vaccine to be promising in the treatment for fungal infections; this vaccine allows the host to restore depressed cellular immunity, minimizing the toxic effects from conventional antifungal therapies. This work was therefore carried out aiming to establish a suitable model for experimental CBM, suggesting also new therapies, including DNA-hsp65 vaccine. By analyzing the morphometrical and histopathological aspects and by quantifying the fungal burden, the results showed the establishment of a chronic, although transitory, experimental CBM model with lesions similar to those presented in humans. A treatment regimen using intralesional itraconazole or amphotericin B was effective in treating experimental CBM, as was a therapy using naked DNA-hsp65 vaccine. It has also been shown that chemotherapy associated with DNA-hsp65 vaccine is promising in the treatment for CBM.

Modulation of the immune response by Fonsecaea pedrosoi morphotypes in the course of experimental chromoblastomycosis and their role on inflammatory response chronicity

“…Footpad infection with F . pedrosoi propagules is already known to establish experimental CBM with skin lesions and histopathological features similar to that found in humans [18,23,42,43] and it is used here as a positive control.…”

“…pedrosoi (ATCC 46428) was cultivated in Sabouraud Dextrose Agar medium (SDA, Himedia) supplemented with 100 mg.l -1 chloramphenicol at 37°C, as described previously [23]. Fungal virulence and strain adaptation to an animal host was acquired by sequentially inoculating F .…”

Chromoblastomycosis

“…After prolonged use, a lichenoid infiltrate may develop as a reflection of increased local immunity. Siqueira et al (315) developed an experimental DNA-hsp65 vaccine to stimulate adaptive immunity, with promising results not only for therapy but also for CBM prophylaxis in animal models. This drug has been combined with itraconazole, with an important improvement of experimental cutaneous lesions (315).…”

Combined immunization using DNA-Sm14 and DNA-Hsp65 increases CD8+ memory T cells, reduces chronic pathology and decreases egg viability during Schistosoma mansoniinfection

“…Our group has previously reported the immunostimulatory properties of the Mycobacterium leprae 65-kDa heat-shock protein (DNA-Hsp65), which is protective against M. tuberculosis [17-19] and effective as an immunomodulatory agent in several diseases, such as leishmaniasis [20], paracoccidioidomycosis [21], chromoblastomycosis [22], diabetes [23], arthritis [24], allergy [25] and phase I cancer trials [26,27]. Our group also reported that in a model of S. mansoni egg-induced fibrosis, the administration of DNA-Hsp65 reduced fibrotic processes during granuloma formation and led to a decrease in collagen deposition at the injury site [28].…”