Human Lobomycosis Caused by Paracoccidioides (Lacazia) loboi, Panama, 2022.

We report a patient from Panama who had lobomycosis caused by Paracoccidioides (Lacazia) loboi. We used combined clinical-epidemiologic and phylogenetic data, including a new gene sequence dataset on this fungus in Panama, for analysis. Findings contribute useful insights to limited knowledge of this fungal infection in the Mesoamerican Biologic Corridor.

Skin fibrosis associated with keloid, scleroderma and Jorge Lobo's disease (lacaziosis): An immuno-histochemical study.

Fibrosis is a common pathophysiological response of many tissues and organs subjected to chronic injury. Despite the diverse aetiology of keloid, lacaziosis and localized scleroderma, the process of fibrosis is present in the pathogenesis of all of these three entities beyond other individual clinical and histological distinct characteristics. Fibrosis was studied in 20 samples each of these three chronic cutaneous inflammatory diseases. An immunohistochemical study was carried out to explore the presence of α-smooth muscle actin (α-SMA) and vimentin cytoskeleton antigens, CD31, CD34, Ki67, p16; CD105, CD163, CD206 and FOXP3 antigens; and the central fibrotic cytokine TGF-ß. Higher expression of vimentin in comparison to α-SMA in all three lesion types was found. CD31- and CD34-positive blood vessel endothelial cells were observed throughout the reticular dermis. Ki67 expression was low and almost absent in scleroderma. p16-positive levels were higher than ki67 and observed in reticular dermis of keloidal collagen in keloids, in collagen bundles in scleroderma and in the external layers of the granulomas in lacaziosis. The presence of α-actin positive cells and rarely CD34 positive cells, observed primarily in keloids, may be related to higher p16 antigen expression, a measure of cell senescence. Low FOXP3 expression was observed in all lesion types. CD105-positive cells were mainly found in perivascular tissue in close contact with the adventitia in keloids and scleroderma, while, in lacaziosis, these cells were chiefly observed in conjunction with collagen deposition in the external granuloma layer. We did not find high involvement of CD163 or CD206-positive cells in the fibrotic process. TGF-ß was notable only in keloid and lacaziosis lesions. In conclusion, we have suggested vimentin to be the main myofibroblast general marker of the fibrotic process in all three studied diseases, while endothelial-to-mesenchymal transition (EndoMT) and mesenchymal stem cells (MSCs) and M2 macrophages may not play an important role.

Lobomycosis Epidemiology and Management: The Quest for a Cure for the Most Neglected of Neglected Tropical Diseases.

Lobomycosis is a chronic disease caused by Lacazia loboi, which is endemic to the Amazon rainforest, where it affects forest dwellers in Brazil. There is no disease control program and no official therapeutic protocol. This situation contributes to an unknown disease prevalence and unmet needs of people disabled by this disease who seek access to treatment. This review provides an update on the subject with an emphasis on therapeutic advances in humans. All relevant studies that addressed epidemiology, diagnosis, or therapeutics of lobomycosis were considered. Seventy-one articles published between 1931 and 2021 were included for a narrative literature review on the epidemiology and quest for a cure. An effective therapy for lobomycosis has been found following decades of research led by the State Dermatology Program of Acre in the Amazon rainforest, where the largest number of cases occur. This discovery opened new avenues for future studies. The main recommendations here, addressed to the Brazilian Ministry of Health, are for lobomycosis to become a reportable disease to ensure that disease prevalence is measured, and that it be prioritized such that affected individuals may access treatment free-of-charge.

Lobomycosis epidemiology and management: the quest for a cure for the most neglected of neglected tropiocal diseases

Lobomycosis is a chronic disease caused by Lacazia loboi, which is endemic to the Amazon rainforest, where it affects forest dwellers in Brazil. There is no disease control program and no official therapeutic protocol. This situation contributes to an unknown disease prevalence and unmet needs of people disabled by this disease who seek access to treatment. This review provides an update on the subject with an emphasis on therapeutic advances in humans. All relevant studies that addressed epidemiology, diagnosis, or therapeutics of lobomycosis were considered. Seventy-one articles published between 1931 and 2021 were included for a narrative literature review on the epidemiology and quest for a cure. An effective therapy for lobomycosis has been found following decades of research led by the State Dermatology Program of Acre in the Amazon rainforest, where the largest number of cases occur. This discovery opened new avenues for future studies. The main recommendations here, addressed to the Brazilian Ministry of Health, are for lobomycosis to become a reportable disease to ensure that disease prevalence is measured, and that it be prioritized such that affected individuals may access treatment free-of-charge.

M2-Polarized Macrophages Determine Human Cutaneous Lesions in Lacaziosis.

Lacaziosis is a cutaneous chronic mycosis caused by Lacazia loboi. Macrophages are important cells in the host immune response in fungal infections. The macrophage population exhibits strong plasticity that varies according to the stimuli in the microenvironment of lesions M1 profile promotes a Th1 pattern of cytokines and a microbicidal function and M2 is related to Th2 cytokines and immunomodulatory response. We investigated the population of M1 and M2 polarized macrophages in human cutaneous lesions. A total of 27 biopsies from human lesions were submitted to an immunohistochemistry protocol using antibodies to detect M1 and M2 macrophages (Arginase-1, CD163, iNOS, RBP-J and cMAF). We could observe high number of cells expressing Arginase1, CD163 and c-MAF that correspond to elements of the M2 profile of macrophage, over iNOS and RBP-J (elements of the M1 profile). The results suggest a predominant phenotype of M2 macrophages, which have an immunomodulatory role and probably contributing to chronicity of Lacaziosis.

Lobomycosis in Soldiers, Colombia.

Lobomycosis is a disease that is endemic to the Amazon rainforest and is caused by the still uncultured fungus Lacazia loboi. This disease occurs in loggers, farmers, miners, fishermen, and persons living near coastal rivers of this region. We report 6 soldiers in Colombia in whom lobomycosis developed after military service in the Amazon area. The patients had nodular and keloid-like lesions on the face, neck, trunk, and limbs. The duration of illness ranged from 2 years to 15 years. The initial diagnosis was leishmaniasis on the basis of clinical manifestations and direct smear results, but biopsies confirmed the final diagnosis of lobomycosis. Treatment with surgical excision, itraconazole and clofazimine was satisfactory. However, the follow-up time was short. Healthcare professionals responsible for the diagnosis and treatment of skin diseases need to be able to recognize the clinical signs of lobomycosis and differentiate them from those of cutaneous leishmaniasis.

Trichosporon asteroides Isolated from Cutaneous Lesions of a Suspected Case of "paracoccidioidomycosis ceti" in a Bottlenose Dolphin (Tursiops truncatus).

"Paracoccidioidomycosis ceti" is a rare zoonotic fungal infection affecting dolphins and is endemic worldwide. The causative agents are Paracoccidioides species; however, it is impossible to isolate the fungal species. We isolated Trichosporon asteroides from multifocal, irregularly raised skin lesions on a female bottlenose dolphin (Tursiops truncatus) captured off coast of Japan, which was suspected to have "paracoccidioidomycosis ceti." An abundance of round, yeast-like cells was detected in a potassium hydroxide direct-mount specimen of the skin samples; however, nested PCR targeting the partial sequence of 43-kDa glycoprotein-coding gene correspondent to Paracoccidioides sp. was negative. Biopsied tissue samples were cultured on brain heart infusion agar plates supplemented with chloramphenicol, 1% yeast extract, and 4% sodium chloride (4% NaCl-BHI), on Mycosel agar with 4% sodium chloride (4% NaCl-Mycosel), and on potato dextrose agar supplemented with chloramphenicol (CPDA) at 35 °C for 4 weeks. Cream-colored and wrinkled colonies consisting of hyphae and arthroconidia grew on 4% NaCl-BHI and CPDA, while film-like colonies composed of arthroconidia and round yeast-like cells developed on 4% NaCl-Mycosel. Although these primary cultures resembled fresh isolates of P. brasiliensis, they were identified as Trichosporon asteroides based on routine mycological studies and the internal transcribed spacer regions of ribosomal RNA sequences. The results suggested that trichosporonosis caused by T. asteroides might remain latent among cases of "paracoccidioidomycosis ceti" diagnosed without cultures and molecular biological analysis.

Cutaneous Granulomas in Dolphins Caused by Novel Uncultivated Paracoccidioides brasiliensis.

Cutaneous granulomas in dolphins were believed to be caused by Lacazia loboi, which also causes a similar disease in humans. This hypothesis was recently challenged by reports that fungal DNA sequences from dolphins grouped this pathogen with Paracoccidioides brasiliensis. We conducted phylogenetic analysis of fungi from 6 bottlenose dolphins (Tursiops truncatus) with cutaneous granulomas and chains of yeast cells in infected tissues. Kex gene sequences of P. brasiliensis from dolphins showed 100% homology with sequences from cultivated P. brasiliensis, 73% with those of L. loboi, and 93% with those of P. lutzii. Parsimony analysis placed DNA sequences from dolphins within a cluster with human P. brasiliensis strains. This cluster was the sister taxon to P. lutzii and L. loboi. Our molecular data support previous findings and suggest that a novel uncultivated strain of P. brasiliensis restricted to cutaneous lesions in dolphins is probably the cause of lacaziosis/lobomycosis, herein referred to as paracoccidioidomycosis ceti.

Detection of Multiple Budding Yeast Cells and a Partial Sequence of 43-kDa Glycoprotein Coding Gene of Paracoccidioides brasiliensis from a Case of Lacaziosis in a Female Pacific White-Sided Dolphin (Lagenorhynchus obliquidens).

Lacaziosis, formerly called as lobomycosis, is a zoonotic mycosis, caused by Lacazia loboi, found in humans and dolphins, and is endemic in the countries on the Atlantic Ocean, Indian Ocean and Pacific Ocean of Japanese coast. Susceptible Cetacean species include the bottlenose dolphin (Tursiops truncatus), the Indian Ocean bottlenose dolphin (T. aduncus), and the estuarine dolphin (Sotalia guianensis); however, no cases have been recorded in other Cetacean species. We diagnosed a case of Lacaziosis in a Pacific white-sided dolphin (Lagenorhynchus obliquidens) nursing in an aquarium in Japan. The dolphin was a female estimated to be more than 14 years old at the end of June 2015 and was captured in a coast of Japan Sea in 2001. Multiple, lobose, and solid granulomatous lesions with or without ulcers appeared on her jaw, back, flipper and fluke skin, in July 2014. The granulomatous skin lesions from the present case were similar to those of our previous cases. Multiple budding and chains of round yeast cells were detected in the biopsied samples. The partial sequence of 43-kDa glycoprotein coding gene confirmed by a nested PCR and sequencing, which revealed a different genotype from both Amazonian and Japanese lacaziosis in bottlenose dolphins, and was 99 % identical to those derived from Paracoccidioides brasiliensis; a sister fungal species to L. loboi. This is the first case of lacaziosis in Pacific white-sided dolphin.

Disseminated infection with Lacazia loboi and immunopathology of the lesional spectrum.

The pathogenesis of lacaziosis continues to be obscure, and works have investigated the blood systemic immune response or the dermal immune response in restricted lesions in different body regions. Some authors describe that the inflammatory infiltrate in lacaziosis lesions showed a predominance of macrophages followed by CD45RO(+), CD4(+), and CD8(+) T cells; CD57(+) natural killer cells; S-100(+) cells; and CD20(+) B lymphocytes. A 54-year-old man and living in the State of Para, Amazon region, Brazil, was seen with a lesion on the left lower limb, which had started as a small nodular area 18 years ago. The lesion showed progressive growth and disseminated to other parts of the body. Our findings showed that dermal immune response differs depending on the type of lesions and clinical presentation, with presence of CD1a(+), FXIIIa(+), CD45(+), CD4(+), CD8(+), and S-100(+) cells and cytokine profile with expression of interleukin 1 ß, tumor necrosis factor α, transforming growth factor ß, IL-10, and interferon γ.

Lobomycosis: epidemiology, clinical presentation, and management options.

Lobomycosis is a subcutaneous mycosis of chronic evolution caused by the Lacazia loboi fungus. Its distribution is almost exclusive in the Americas, and it has a particularly high prevalence in the Amazon basin. Cases of lobomycosis have been reported only in dolphins and humans. Its prevalence is higher among men who are active in the forest, such as rubber tappers, bushmen, miners, and Indian men. It is recognized that the traumatic implantation of the fungus on the skin is the route by which humans acquire this infection. The lesions affect mainly exposed areas such as the auricles and upper and lower limbs and are typically presented as keloid-like lesions. Currently, surgical removal is the therapeutic procedure of choice in initial cases. Despite the existing data and studies to date, the active immune mechanisms in this infection and its involvement in the control or development of lacaziosis have not been fully clarified. In recent years, little progress has been made in the appraisal of the epidemiologic aspects of the disease. So far, we have neither a population-based study nor any evaluation directed to the forest workers.

Plasmacytoid dendritic cells in cutaneous lesions of patients with chromoblastomycosis, lacaziosis, and paracoccidioidomycosis: a comparative analysis.

Plasmacytoid dendritic cells (pDCs) are characterized by expression of CD123 and BDCA-2 (Blood Dendritic Cell Antigen 2) (CD303) molecules, which are important in innate and adaptive immunity. Chromoblastomycosis (CBM), lacaziosis or Jorge Lobo's disease (JLD), and paracoccidioidomycosis (PCM), are noteworthy in Latin America due to the large number of reported cases. The severity of lesions is mainly determined by the host's immune status and in situ responses. The dendritic cells studied in these fungal diseases are of myeloid origin, such as Langerhans cells and dermal dendrocytes; to our knowledge, there are no data for pDCs. Forty-three biopsies from patients with CBM, 42 from those with JLD and 46 diagnosed with PCM, were evaluated by immunohistochemistry. Plasmacytoid cells immunostained with anti-CD123 and anti-CD303 were detected in 16 cases of CBM; in those stained with anti-CD123, 24 specimens were obtained from PCM. We did not detect the presence of pDCs in any specimen using either antibody in JLD. We believe that, albeit a secondary immune response in PCM and CBM, pDCs could act as a secondary source of important cytokines. The BDCA-2 (CD303) is a c-type lectin receptor involved in cell adhesion, capture, and processing of antigens. Through the expression of the c-lectin receptor, there could be an interaction with fungi, similar to other receptors of this type, namely, CD207 in PCM and CD205 and CD209 in other fungal infections. In JLD, the absence of expression of CD123 and CD303 seems to indicate that pDCs are not involved in the immune response.

Lobomycosis: A case from Southeastern Europe and review of the literature.

BACKGROUND: Lobomycosis, also known as Jorge Lobo's disease, represents a rare chronic subcutaneous mycosis caused by the fungus Lacazia loboi, an organism that is found within lesions but has not been cultured to date. The natural reservoir of L. loboi is unknown but it is believed to be aquatic, or associated with soil and vegetation. More than 550 human cases have been reported, especially in patients with a history of travel or residence in endemic areas (Central and South America, particularly Brazil) or in communities along rivers. MAIN OBSERVATIONS: We describe a 64-year-old Greek female farmer living in a coastal region, who presented with an erythematous plaque on her left inner thigh resembling a keloid. The diagnosis was based on the triad: 1) absence of fungal growth in cultures, 2) positive direct microscopic examination of the lesion and 3) histopathology, all consistent with lobomycosis. Particularly, skin biopsy showed deep cutaneous fungal infection with granulomatous reaction. Fungal cells were found inside giant cells. The fungi were thick-walled with some budding, isolated or in short chains. Dermal fibrosis was present. Our patient had a medical history of common variable immunodeficiency but no history of travel to South or Central America. She probably acquired this rare infection by injury during her agricultural works. CONCLUSION: Our case represents probably the first documented case of human lobomycosis in Southeastern Europe. This case is unusual due to the rarity of lobomycosis in Mediterranean countries, particularly in Southeastern Europe.

Determinação dos níveis séricos de lectina ligada a manose e citocinas em pacientes de lacaziose e a associação destes com as formas clínicas da doença / Determination of serum levels of mannose binding lectin and cytokines in lacaziosis patients and the association of them with the clinical forms of disease

A lacaziose é uma micose cutânea – subcutânea de evolução crônica, cujo agente etiológico é a Lacazia loboi (L. loboi). A suscetibilidade a infecção e desenvolvimento da doença pode se manifestar diferentemente de um indivíduo para outro. Isto pode ser atribuído a inúmeros fatores como a deficiência de lectina ligada a manose – MBL (mannose binding lectin) e distúrbios no equilíbrio da produção e liberação das citocinas. No entanto, entre MBL e doenças fúngicas poucos estudos são encontrados na literatura, assim como para algumas determinações séricas de citocinas. Diante disso, a análise da associação entre as manifestações clínicas e níveis séricos destes mediadores é de fundamental importância para avaliar o padrão de resposta imune inata e adaptativa nos portadores de lacaziose da região de Rio branco (AC). Assim, o objetivo deste estudo foi avaliar os níveis séricos de MBL e das citocinas (IL-4, IL-6, IL-10, IL-17, IL-22, TGF-Beta1 e IFN-Gama) em pacientes com a doença nas suas distintas formas clínicas...

Lacaziosis is a cutaneous – subcutaneous mycosis of chronic evolution, whose etiologic agent is Lacazia loboi (L. loboi). The infection susceptibility and disease development can manifest differently in one individual to another. It can be due to many factors, like the deficiency of mannose binding lectin - MBL and disturb the balance of the production and release of cytokines. However, few studies are found in the literature of MBL and fungal diseases and likewise some on serum cytokines determinations. The analysis of the association between clinical manifestations and serum levels of these mediators is of fundamental importance in evaluating the standard of innate and adaptive immune response of the Jorge Lobo’s disease patients the of Rio Branco (AC) region. Through carrying out this type of analysis, the objective of this study was to evaluate serum levels of MBL and cytokines (IL-4, IL-6, IL-10, IL-17, IL-22, TGF-Beta1 and IFN-Gamma) in patients with disease in their distinct clinical form...

Molecular phylogeny of animal pathogen Lacazia loboi inferred from rDNA and DNA coding sequences

Lacazia loboi is a geographically restricted, uncultivated fungal pathogen of humans and dolphins. Previous investigations using 18S small unit rDNA, chitin synthase 2 and gp43 DNA sequences positioned L. loboi as a close relative of Paracoccidioides brasiliensis. However, given the few individuals of L. loboi studied and the high degree of genetic variation observed in P. brasiliensis, the existence of L. loboi as an independent species has been questioned. To investigate the phylogenetic position of this species, we conducted a phylogenetic analysis using 20 L. loboi collections (L. loboi was obtained from proven cases of lacaziosis and 14 collections were maintained in mice, the others were analyzed from DNA taken directly from infected human tissue.). L. loboi DNA sequence was compared to that from 17 P. brasiliensis strains that represented the known variation in this species, and outgroup taxa in the Onygenales (Ajellomyces and Coccidioides species). Our analyses used DNA sequence from ITS rRNA, and partial coding sequences of chitin synthase 4, ADP-ribosylation factor, and gp43. Nucleotide variation among strains of L. loboi was minor but numerous nucleotide mismatches and multiple gaps were found for these gene regions among members in the Ajellomycetaceae, including P. brasiliensis. Phylogenies inferred using neighbor-joining, maximum parsimony and Bayesian analyses showed no significant conflict and depicted L. loboi as a well-supported, monophyletic group that was sister to the Paracoccidioides clade. These results argue for maintaining L. loboi as a taxon independent from Paracoccidioides within the Ajellomycetaceae.