Chromoblastomycosis is a chronic fungal infection primarily affecting the skin and subcutaneous tissues. It is caused by several species of dematiaceous fungi such as Cladophialophora, Exophiala, Fonsecaea, Phialophora, and Rhinocladiella. F. pedrosoi, F. monophora, and F. nubica represent three cryptic entities that could induce the same disease [1] [2] [3] [4]. Fonsecaea pedrosoi and F. nubica are associated with muriform cell formation in chromoblastomycosis, whereas F. monophora could be involved in dissemination to the brain and other organs with hyphae in tissue [5]. Recently, some cases have been confirmed caused by Fonsecaea monophora [6] [7]. These fungi are found in soil, decaying vegetation, and wood, particularly in tropical and subtropical regions.
The infection typically begins following traumatic inoculation of fungal spores into the skin, often through minor injuries like cuts, scratches, or thorn pricks. Once inoculated, the fungi establish a chronic infection characterized by the formation of verrucous or nodular lesions on exposed areas of the body, most commonly the lower extremities. [8] [9]. In general, the treatment of chromoblastomycosis is a therapeutic challenge because various methods and antimicrobials are used in attempts to cure or control the disease, but most of them fail. There are many cases of relapse and few reports of ultimate cures [4] [10].
The immune response to chromoblastomycosis involves both innate and adaptive components. Our laboratory showed that PBMC from patients with severe forms of chromoblastomycosis failed to proliferate in vitro after induction with chromoAg and produced high levels of IL-10 and low levels of IFN-γ [11]. In contrast, cells from patients with mild forms of the disease efficiently induced T-cell proliferation and IFN-γ production. These results suggest that the Th1 response is essential to induce protective immunity during chromoblastomycosis.
The recognition of pathogens is a severe challenge to the innate immune system due to the enormous variability and characteristically high rate of mutation of microorganisms. However, the innate immune system has evolved receptors, which target molecular structures common to large groups of pathogens or produced by pathogens, not the host. These structures are called pathogen-associated molecular patterns (PAMPs). The PAMPs are recognized by receptors called pattern recognition receptors (PRRs). Members of several family proteins function as PRRs and are expressed in cells responsible for the first line of defense of the body, such as macrophages and dendritic cells [12]. Caspase-1 is produced as a zymogen, called pro-caspase-1, cleaved into two subunits of 20-kDa (p20) and 10 kDa (p10). This event transforms the zymogen into an active enzyme that can cleave proteins at specific regions, such as the IL-1β and IL-18 cytokines [13] [14]. Interleukin-18 (IL-18) is a pro-inflammatory cytokine that plays a crucial role in regulating immune responses, particularly those involving T cells and natural killer (NK) cells. It is a member of the interleukin-1 (IL-1) superfamily and is produced by various cell types, including macrophages, dendritic cells, epithelial cells, and endothelial cells, in response to microbial products, inflammatory stimuli, or other cytokines.
IL-18 is synthesized as an inactive precursor protein (pro-IL-18) and requires proteolytic processing by caspase-1, which is activated by multiprotein complexes known as inflammasomes, to become biologically active [15]. The primary function of IL-18 is to induce the production of interferon-gamma (IFNγ), another important pro-inflammatory cytokine, mainly from T cells and NK cells. This makes IL-18 a potent inducer of Th1 responses, which are characterized by the activation of CD4 + T cells to produce IFNγ and promote cell-mediated immunity against intracellular pathogens, including bacteria, viruses, and fungi.
Our laboratory [16] showed that macrophages infected by F. pedrosoi and R. aquaspersa, the etiological agents of chromoblastomycosis, induced the production of inflammatory cytokines such as IL-1β and TNF-a. De Castro et al. 2017, showed that F. pedrosoi hyphae, induce IL-1β secretion in bone marrow-derived dendritic cells and macrophages. IL-1β production was NLRP3-dependent inflammasome activation, which required potassium efflux, reactive oxygen species production, phagolysosomal acidification, and cathepsin B release as triggers. However, there is no data on the importance of IL-18 in activating Th cells during chromoblastomycosis. Our results indicate that F. pedrosoi is sensed by the NLRP3 inflammasome, which induces caspase-1 activation and a proinflammatory response. Moreover, we showed that IL-18 is required to activate the Th1 response and control fungal loads during chromoblastomycosis.