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Chromoblastomycosis (CBM) is a chronic, neglected tropical fungal infection. Its immunopathogenesis, particularly the mechanism underlying its chronicity, remains poorly understood. We performed single-cell RNA sequencing (scRNA-seq) on lesional skin from a CBM patient, followed by comprehensive bioinformatics analyses. We then used multiplex immunofluorescence (mIF) to validate CD4 T cell exhaustion in CBM patient lesions and the mouse model of infection. We identified a significantly expanded population of exhausted CD4 T cells within the patient's lesions, which exhibited high co-expression of inhibitory receptors (PD-1, TIM-3, LAG-3) and functional impairment. Trajectory inference suggested a differentiation path from naive towards exhaustion within the chronic inflammatory environment. Cell-cell communication analysis implicated monocytes/macrophages (MoMacs) as key drivers of this process via persistent antigen presentation and ligand-receptor interactions such as CTLA4-CD80/86 and LGALS9-CD44. The accumulation of exhausted CD4 T cells was confirmed in human CBM lesions by multiplex immunofluorescence (mIF), and the progressive development of exhaustion was recapitulated in the mouse model of infection. Our findings establish CD4 T cell exhaustion as an important mechanism underlying the chronicity of chromoblastomycosis, revealing a new immunopathological perspective for this neglected disease.

Chromoblastomycosis is a chronic fungal infection characterized by the formation of granulomatous lesions in the skin and subcutaneous tissues that begins after inoculation trauma. The disease is more frequently observed in tropical countries such as Brazil. Important studies have been shown a predominantly cell-mediated immune response during chromoblastomycosis. Results from our laboratory showed that Th1 responses are essential to induce protection during chromoblastomycosis. IL-18 is primarily produced by macrophages and is known to induce the production of IFNγ, a cytokine associated with Th1 cell activation. Once produced, IL-18 acts to promote Th1 cell differentiation and activation. Th1 cells, in turn, secrete cytokines such as IFNγ, which are critical for the elimination of intracellular pathogens, including fungi. IFNγ enhances the fungicidal activity of macrophages, promotes the development of antifungal effector mechanisms, and contributes to the containment of fungal growth. Our results indicate that F. pedrosoi is sensed by the NLRP3 inflammasome, which induces caspase-1 activation and production of IL-18. Moreover, IL-18 plays a crucial role in activating Th1 cells and controlling fungal loads during chromoblastomycosis. Further research into the mechanisms underlying IL-18-mediated immunity may lead to the development of novel therapeutic approaches for the treatment of this chronic fungal infection.

Chromoblastomycosis is a chronic and progressive subcutaneous mycosis caused mainly by the fungus . The infection is characterized by erythematous papules and histological sections demonstrating an external layer of fibrous tissue and an internal layer of thick granulomatous inflammatory tissue containing mainly macrophages and neutrophils. Several groups are studying the roles of the innate and adaptive immune systems in infection; however, few studies have focused on the role of neutrophils in this infection. In the current study, we verify the importance of murine neutrophils in the killing of conidia and hyphae. We demonstrate that phagocytosis and reactive oxygen species during infection with conidia are TLR-2- and TLR-4-dependent and are essential for conidial killing. Meanwhile, hyphal killing occurs by NET formation in a TLR-2-, TLR-4-, and ROS-independent manner. In vivo experiments show that TLR-2 and TLR-4 are also important in chromoblastomycosis infection. TLR-2KO and TLR-4KO animals had lower levels of CCL3 and CXCL1 chemokines and impaired neutrophil migration to the infected site. These animals also had higher fungal loads during infection with conidia, confirming that TLR-2 and TLR-4 are essential receptors for recognition and immune system activation. Therefore, this study demonstrates for the first time that neutrophil activation during is conidial or hyphal-specific with TLR-2 and TLR-4 being essential during conidial infection but unnecessary for hyphal killing by neutrophils.

Chromoblastomycosis (CBM), a chronic subcutaneous infection caused by black fungi such as Fonsecaea monophora ( F. monophora ), is characterized by a low cure rate, high recurrence rate, and prolonged treatment duration. Neutrophils, one of the most important innate immune cells, play complex roles in the prevention of fungal infections. This study investigated the function of neutrophils in host defense against F. monophora using a neutrophil-depleted mouse model and in vitro co-culture conditions. Fungal burden, histopathological changes, and cytokine profiles were compared between neutrophil-depleted mice and isotype control mice. Our findings demonstrated that neutrophil depletion in mice led to impaired fungal clearance, prolonged inflammation in F. monophora infected footpad tissues, highlighting the critical role of neutrophils in controlling F. monophora infection. Histopathological analysis revealed extensive inflammatory cell infiltration, especially macrophages, accompanied by elevated levels of pro-inflammatory cytokines such as IL-1β, CCL3, IL-6, and TNF-α. Besides, we observed that neutrophils play a key role in inhibiting the morphological transition of F. monophora from conidia to hyphae and sclerotic-like cells. Notably, the F. monophora morphology was also associated with the formation of neutrophil extracellular traps (NETs) in in vitro experiment. These findings underscore the importance of neutrophil-mediate immune responses in early fungal clearance and their ability to influence F.monophora morphological transition. The study provides novel insights into the immune mechanisms underlying CBM and highlights the potential therapeutic implications of targeting neutrophil-mediated responses in CBM infections.

Chromoblastomycosis in intracranial locations is extremely rare in immunocompetent hosts. Neurotropism of fungal elements has been reported in the literature mostly in immunocompromised individuals. We report a case of a 36-year-old industrial worker with disseminated untreated skin lesions and presenting with cerebellar symptoms and space-occupying lesion in the left cerebellar hemisphere. Histopathological examination revealed a diagnosis of cerebellar chromoblastomycosis. To our knowledge, this is the first reported case of cerebellar chromoblastomycosis in an immunocompetent individual.

Chromoblastomycosis (CBM) is a chronic cutaneous infection caused by dematiaceous fungi, characterized by therapeutic challenges such as difficulty in pathogen clearance and high recurrence rates. ( ), the most common etiological agent of CBM, relies on its virulence factor DHN-melanin to evade host immune responses-especially by suppressing neutrophil function-further contributing to disease persistence and treatment resistance. Thus, we intended to explore therapeutic approaches that target both fungal virulence mechanisms and host immune regulation to overcome the clinical hurdles of CBM. This study aimed to investigate the effects of tricyclazole (TCZ) on and neutrophil antifungal responses, with a particular focus on its potential actions in inhibiting DHN-melanin synthesis and enhancing host oxidative immune mechanisms. We conducted assays to assess the effects of TCZ on melanin and fungal antioxidant enzymes, as well as reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) formation in human neutrophils. The mouse model was used to evaluate inflammatory responses, neutrophil-related markers, and fungal clearance. tests showed TCZ dose-dependently inhibited fungal DHN-melanin synthesis and disrupted the antioxidant enzyme system (including superoxide dismutase and catalase); this effect not only weakens the fungus's ability to resist host oxidative stress but also reduces its capacity to evade immune recognition, creating conditions for subsequent immune clearance. co-culture models revealed that TCZ significantly enhanced neutrophil ROS production and NET formation; this strengthens the oxidative killing function of neutrophils, directly counteracting the immunosuppressive effect of DHN-melanin on neutrophils and improving the host's ability to eliminate pathogens. In a mouse infection model, TCZ treatment significantly alleviated pedal inflammation, reduced neutrophil activation markers, and completely eliminated fungal colonization; these results validate TCZ's therapeutic efficacy, demonstrating its potential to mitigate inflammatory tissue damage while achieving effective fungal eradication. This study reveals a novel mechanism by which TCZ counteracts -mediated suppression of neutrophil antifungal effector functions, particularly oxidative burst and NET formation, thereby facilitating fungal clearance in CBM. These findings provide a novel strategy for CBM treatment by integrating immunomodulation with antifungal therapy.

Chromoblastomycosis (CBM) is a chronic worldwide subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. It is difficult to treat patients with the disease, mainly because of its recalcitrant nature. The correct activation of host immune response is critical to avoid fungal persistence in the tissue and disease chronification. CD4+ T cells are crucial for the development of protective immunity to F. pedrosoi infection. Here, we investigated T helper cell response dynamics during experimental CBM. Following footpad injection with F. pedrosoi hyphae and conidia, T cells were skewed towards a Th17 and Th1 phenotype. The Th17 population was the main Th cell subset found in the infected area during the early stages of experimental murine CBM, followed by Th1 predominance in the later stages, coinciding with the remission phase of the disease in this experimental model. Depletion of CD25+ cells, which leads to a reduction of Treg cells in the draining lymph node, resulted in decline in fungal burden after 14 days of infection. However, fungal cells were not cleared in the later stages of the disease, prolonging CBM clinical features in those animals. IL-17A and IFN-γ neutralization hindered fungal cell elimination in the course of the disease. Similarly, in dectin-2 KO animals, Th17 contraction in the course of experimental CBM was accompanied by fungal burden decrease in the first 14 days of infection, although it did not affect disease resolution. In this study, we gained insight into T helper subsets' dynamics following footpad injections of F. pedrosoi propagules and uncovered their contribution to disease resolution. The Th17 population proved to be important in eliminating fungal cells in the early stages of infection. The Th1 population, in turn, closely assisted by Treg cells, proved to be relevant not only in the elimination of fungal cells at the beginning of infection but also essential for their complete elimination in later stages of the disease in a mouse experimental model of CBM.

Chromoblastomycosis (CBM) is a neglected human disease, caused by different species of pigmented dematiaceous fungi that cause subcutaneous infections. This disease has been considered an occupational disease, occurring among people working in the field of agriculture, particularly in low-income countries. In 1914, the first case of CBM was described in Brazil, and although efforts have been made, few scientific and technological advances have been made in this area. In the field of fungi and host cell relationship, a very reduced number of antigens were characterized, but available data suggest that ectoantigens bind to the cell membrane of host cells and modulate the phagocytic, immunological, and microbicidal responses of immune cells. Furthermore, antigens cleave extracellular proteins in tissues, allowing fungi to spread. On the contrary, if phagocytic cells are able to present antigens in MHC molecules to T lymphocytes in the presence of costimulation and IL-12, a Th1 immune response will develop and a relative control of the disease will be observed. Despite knowledge of the resistance and susceptibility in CBM, up to now, no effective vaccines have been developed. In the field of chemotherapy, most patients are treated with conventional antifungal drugs, such as itraconazole and terbinafine, but these drugs exhibit limitations, considering that not all patients heal cutaneous lesions. Few advances in treatment have been made so far, but one of the most promising ones is based on the use of immunomodulators, such as imiquimod. Data about a standard treatment are missing in the medical literature; part of it is caused by the existence of a diversity of etiologic agents and clinical forms. The present review summarizes the advances made in the field of CBM related to the diversity of pathogenic species, fungi and host cell relationship, antigens, innate and acquired immunity, clinical forms of CBM, chemotherapy, and diagnosis.

Neutrophils are essential to control several fungal infections. These cells are commonly known for their pro-inflammatory activities. However, some studies have demonstrated the anti-inflammatory properties of neutrophils during certain infectious diseases, culminating in the inhibition of T cell proliferation. Chromoblastomycosis (CBM) is a deep and progressive mycosis that affects thousands of people worldwide. Although neutrophil infiltrates are observed in the lesion histopathology, the fungus can overtake the immune system response and destroy the host-infected tissue. The present study demonstrated that neutropenic animals had an increase in the IL-6 production in the spleen and liver, followed by a lower fungal burden in these organs up to 14 days of infection. Neutropenic animals also showed a lower F. pedrosoi -specific antibody production 14-days post infection and higher T-cell proliferation in the in vitro experiments after stimulation with F. pedrosoi -purified proteins. Taken together, our results suggest that the presence of regulatory neutrophils in the mouse model of F. pedrosoi infection could act favoring the spread of the fungus and the chronicity of the infection. These findings shed light on the CBM treatment, which might target neutrophil polarization as a new therapy approach to treat CBM lesions.

A common theme across multiple fungal pathogens is their ability to impair the establishment of a protective immune response. Although early inflammation is beneficial in containing the infection, an uncontrolled inflammatory response is detrimental and may eventually oppose disease eradication. Chromoblastomycosis (CBM), a cutaneous and subcutaneous mycosis, caused by dematiaceous fungi, is capable of inducing a chronic inflammatory response. Muriform cells, the parasitic form of Fonsecaea pedrosoi, are highly prevalent in infected tissues, especially in long-standing lesions. In this study we show that hyphae and muriform cells are able to establish a murine CBM with skin lesions and histopathological aspects similar to that found in humans, with muriform cells being the most persistent fungal form, whereas mice infected with conidia do not reach the chronic phase of the disease. Moreover, in injured tissue the presence of hyphae and especially muriform cells, but not conidia, is correlated with intense production of pro-inflammatory cytokines in vivo. High-throughput RNA sequencing analysis (RNA-Seq) performed at early time points showed a strong up-regulation of genes related to fungal recognition, cell migration, inflammation, apoptosis and phagocytosis in macrophages exposed in vitro to muriform cells, but not conidia. We also demonstrate that only muriform cells required FcγR and Dectin-1 recognition to be internalized in vitro, and this is the main fungal form responsible for the intense inflammatory pattern observed in CBM, clarifying the chronic inflammatory reaction observed in most patients. Furthermore, our findings reveal two different fungal-host interaction strategies according to fungal morphotype, highlighting fungal dimorphism as an important key in understanding the bipolar nature of inflammatory response in fungal infections.