No abstract

Chromoblastomycosis (CBM) is a neglected, chronic, and progressive subcutaneous mycosis caused by different species of fungi from the Herpotrichiellaceae family. CBM disease is usually associated with agricultural activities, and its infection is characterized by verrucous, erythematous papules, and atrophic lesions on the upper and lower limbs, leading to social stigma and impacts on patients’ welfare. The economic aspect of disease treatment is another relevant issue. There is no specific treatment for CBM, and different anti-fungal drug associations are used to treat the patients. However, the long period of the disease and the high cost of the treatment lead to treatment interruption and, consequently, relapse of the disease. In previous years, great progress had been made in the comprehension of the CBM pathophysiology. In this review, we discuss the differences in the cell wall composition of conidia, hyphae, and muriform cells, with a particular focus on the activation of the host immune response. We also highlight the importance of studies about the host skin immunology in CBM. Finally, we explore different immunotherapeutic studies, highlighting the importance of these approaches for future treatment strategies for CBM.

The immune response against fungal infections is complex and exhibits several factors involving innate elements that participate in the interaction with the fungus. The innate immune system developed pattern recognition receptors that recognize different pathogen-associated molecular patterns present both on the surface of the fungi cell wall and on their genetic material. These receptors have the function of activating the innate immune response and regulating a subsequent adaptive immune response. Among pattern recognition receptors, the family of Toll-like receptors and C-type lectin receptors are the best described and characterized, they act directly in the recognition of pathogen-associated molecular patterns expressed on the wall of the fungus and consequently in directing the immune response. In recent years, the role of intracellular pattern recognition receptors (TLR3, TLR7, TLR8, and TLR9) has become increasingly important in the pathophysiology of some mycoses, as paracoccidioidomycosis, cryptococcosis, aspergillosis, and candidiasis. The recognition of nucleic acids performed by these receptors can be essential for the control of some fungal infections, as they can be harmful to others. Therefore, this review focuses on highlighting the role played by intracellular pattern recognition receptors both in controlling the infection and in the host's susceptibility against the main fungi of medical relevance.

Chromoblastomycosis is a chronic and progressive subcutaneous mycosis caused mainly by the fungus Fonsecaea pedrosoi. The infection is characterized by erythaematous papules and the 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 have been studying the roles of the innate and adaptive immune systems in F. pedrosoi infection; however, few studies have focused on the role of neutrophils in this infection. In the current study, we verified the importance of murine neutrophils in the killing of F. pedrosoi conidia and hyphae. We demonstrate that phagocytosis and reactive oxygen species during infection with conidia are TLR-2 and TLR-4-dependent and are essentials for conidial killing. Meanwhile, hyphal killing occurs by NETs formation, in a TLR-2, TLR-4 and ROS-independent manner. In vivo experiments showed that TLR-2 and TLR-4 are also important in Chromoblastomycosis infection. TLR-2KO and TLR-4KO animals had lower levels of MIP-2 and KC chemokines and impaired neutrophil migration to the infected site. These animals also had higher fungal loads during infection with F. pedrosoi conidia, confirming that TLR-2 and TLR-4 are essential receptors for F. pedrosoi recognition and immune system activation. Therefore, this study demonstrated for the first time that neutrophils activation during F. pedrosoi is conidial or hyphal-specific, with TLR-2 and TLR-4 being essential during conidial infection but unnecessary for hyphal killing by neutrophilsAuthor SummaryChromoblastomycosis (CBM) is a chronic and progressive subcutaneous mycosis that affects mainly low-income individuals, such as farm workers. CBM have been diagnosed all over the world, but the majority of cases were diagnosed in tropical and subtropical climate countries. The treatment is difficult and involves the combination of antifungal prescriptions, cryo/heat-therapy and, in some cases, surgery to remove all the infected tissue. The treatment is long (at least 6 months) and expensive, leading to a high rate of treatment dropout and disease relapse. However, the understanding of pathogen-host interaction is far from being elucitaded. Our understanding is that this pathogen-host interaction in CBM needs to be uncovered so a different and more effective treatment could be proposed to help those patients that are struggling against this chronic infection. Therefore, our study shed a light in neutrophils and innate immune response against this fungal infection, showing the neutrophils capacity to kill Fonsecaea pedrosoi conidia and hifa, showing the importance of toll-like receptors 2 and 4 in the neutrophil fungicidal capacity against F. pedrosoi conidia but not hyphae. Therefore this work help to the better understanding of how our organism fights back in the CBM infection.

PAULO, L. N. M. Avaliação da resposta imune induzida por células dendríticas previamente ativadas com agonistas das vias TLR-2 e TLR-9 na Cromoblastomicose experimental.