Development and evaluation of a rapid diagnostic method for Sporothrix globosa in Asia using quantitative real-time PCR.

BACKGROUND: Sporotrichosis is a chronic granulomatous infection of the skin and subcutaneous tissue that can affect any organ through lymphatic spread. The prevalence of sporotrichosis infections is increasing and its treatment is challenging as there are no unified and standard diagnostic techniques or antifungal medications. Controlling further spread requires a rapid diagnosis. Assessment of clinical symptoms, histological analysis, serological testing, and pathogen culture are all necessary for the diagnosis of sporotrichosis. However, these procedures are unable to identify the species. The development of safe, reliable, and species-specific diagnostic techniques is essential. OBJECTIVE: To establish and evaluate a new quantitative real-time PCR assay for the rapid diagnosis of sporotrichosis and to identify relevant species. METHODS: Polymorphisms in calmodulin (CAL) gene sequences and the internal transcribed spacer (ITS) were used in a quantitative real-time PCR assay to identify S. globosa, S. schenckii, and non-target species. RESULTS: The quantitative real-time PCR assay had 100% sensitivity and specificity. The limit of detection was 6 fg/µl. Thirty-four clinical specimens were verified to be infected with S. globosa with a 100% positive detection rate. CONCLUSIONS: The quantitative PCR technique developed in this study is a quick, accurate, and targeted method of identifying S. globosa based on polymorphisms in CAL sequences and ITS. It can be used for a prompt clinical diagnosis to identify S. globosa in clinical specimens from patients with sporotrichosis.

Systematic review of literature to evaluate global distribution of species of the Sporothrix genus stored in culture collections.

Introduction: Sporotrichosis is a subcutaneous mycosis caused by fungi of the genus Sporothrix sp. Phenotypic and genotypic differences have been associated with their geographic distribution, virulence, or clinical manifestation of sporotrichosis. In the past decade, the interest in identifying species of the Sporothrix sp. has been increasing, due to its epidemiological importance and, in consequence, is important to know how to preserve them for future studies, in culture collection. Aims: The purposes of this study were to analyze the global distribution of environmental isolates and/or causal agents of sporotrichosis identified by polyphasic taxonomy, with mandatory use of molecular identification, and to evaluate the percentages and distribution of isolates stored in culture collections. Methods: A systematic review of articles on animal and human sporotrichosis and/or environmental isolation of the fungus, from 2007 to 2023, was done. Results: Our results demonstrated that, S. globosa, S. schenckii, and S. brasiliensis were the most identified species. With respect to the deposit and maintenance of species, we observed that only 17% of the strains of Sporothrix sp. isolated in the world are preserved in a culture collection. Conclusions: This systematic review confirmed a difficulty in obtaining the frequency of Sporothrix species stored in culture collection and insufficient data on the molecular identification mainly of animal sporotrichosis and isolation of Sporothrix sp. in environmental samples.

Parinaud's oculoglandular syndrome: Coinfection by Bartonella henselae and Sporothrix brasiliensis.

A 26-year-old woman presented an eyelid lesion, after being scratched by a cat that had a similar skin lesion. It evolved into a cervical lymph node enlargement. With a hypothesis of Parinaud´s oculoglandular syndrome (POS) due to cat scratch disease (CSD), doxycycline was prescribed. After two weeks of treatment without improvement, a biopsy and blood sample were obtained. Itraconazole was prescribed and the skin lesion improved, but not the lymph node enlargement. A Sporothrix schenckii complex was isolated from the skin sample. Also, a specie-specific polymerase chain reaction detected Bartonella henselae DNA in her blood sample. Azithromycin was included to treat the bacterial infection, whereupon the lymph node also receded successfully. Sporotrichosis and CSD are zoonoses that can be transmitted to humans by traumatic inoculation due to scratches or bites from cats. Both can evolve with POS. Patients who present skin lesions and/or POS after being wounded by a cat should be investigated for both diseases.

Feline sporotrichosis: Characterization of cutaneous and extracutaneous lesions using different diagnostic methods.

Sporotrichosis is a mycotic infection of the cutaneous and subcutaneous tissues caused by Sporothrix spp. that can also cause extracutaneous manifestations. This study aimed to characterize cutaneous and extracutaneous sporotrichosis lesions in cats. Over 1 year, 102 cats rescued by the Zoonoses Control Center of Belo Horizonte, Brazil, euthanized with clinical suspicion of feline sporotrichosis were evaluated. After euthanasia, the animals were evaluated by macroscopic, cytological, histopathological, and immunohistochemistry (IHC) examinations; fungal culture; and polymerase chain reaction (PCR). Sporothrix infection was identified by at least one diagnostic technique in all cats (n = 102) evaluated by postmortem examination, including 26/28 cases (93%) evaluated by IHC, 66/90 cases (73%) evaluated by cytology, 70/102 cases (68.6%) evaluated by histopathology, and 62/74 cases (84%) evaluated by fungal culture. Two cats had positive results only by fungal culture. Cytology and histopathology examinations were effective in diagnosing sporotrichosis, although IHC was needed to confirm the diagnosis in cats with low fungal loads. Sporothrix brasiliensis was confirmed by the sequencing of 3 samples. Skin lesions were characterized mainly by pyogranulomatous to granulomatous dermatitis (frequently with subcutaneous inflammation) with different intensities of Sporothrix spp. yeast. Extracutaneous findings associated with sporotrichosis included rhinitis or rhinosinusitis, lymphadenitis, pneumonia, meningitis, periorchitis, conjunctivitis, and glossitis. Extracutaneous infections were observed in 74/102 cases, and a possible association between the chronicity of the disease and the higher pathogenicity of this fungal species in cats requires further investigation.

Primer aislamiento de Sporothrix brasiliensis en un caso humano de esporotricosis en Chile. Un hongo emergente y preocupante / First isolation of Sporothrix brasiliensis in a human case of sporotrichosis in Chile. An emerging and worrisome fungus

Se describe el aislamiento de Sporothrix brasiliensis desde una biopsia de piel de un caso humano de esporotricosis linfocutánea, en la región de Valparaíso, Chile. Esta especie es la más virulenta del género y es de transmisión zoonótica, desde los gatos a los humanos. Hasta ahora, solo se había publicado un brote por esta especie en gatos domésticos y asilvestrados en el extremo sur de Chile, por lo que este aislamiento, en una mujer residente de un sector densamente poblado de la Región de Valparaíso, constituye una preocupación por su eventual diseminación hacia otros gatos y la población general.

The isolation of Sporothrix brasiliensis from a skin biopsy of a human case of lymphocutaneous sporotrichosis in the region of Valparaíso, Chile is described. This species is the most virulent of the genus and is zoonotic in transmission from cats to humans. Until now, only one outbreak of this species has been published in domestic and feral cats in the extreme south of Chile, so this isolation in a woman residing in a densely populated sector of the fifth region is a concern for its eventual spread to other cats and the general population.

Intramedullary disseminated sporotrichosis in an immunocompetent patient: case report and review of the literature.

BACKGROUND: Disseminated sporotrichosis is a severe opportunistic infection that often affects immunocompromised patients after a cutaneous inoculation. Here we present a rare case of disseminated sporotrichosis discovered as a solitary intramedullary thoracic spinal cord lesion in an immunocompetent patient. CASE DESCRIPTION: A 37-year-old man presented with progressive lower limb weakness and sensory changes over 1 week. A spinal magnetic resonance imaging (MRI) revealed a contrast-enhancing intramedullary lesion centered at T10. The patient was afebrile and reported no history of trauma or cutaneous lesions. The lesion was unresponsive to a trial of corticosteroids. A thoracic laminectomy was performed and a biopsy obtained. A cutaneous lesion on the arm was concurrently discovered, which was also biopsied. Both the skin and spinal cord biopsies showed Sporothrix schenckii by macroscopic and microscopic morphology which were later confirmed by MALDI-TOF mass spectrometry. CONCLUSION: This is a rare case of intramedullary disseminated sporotrichosis affecting the central nervous system of an immunocompetent patient. This unusual presentation should be taken into consideration when such intramedullary lesions are encountered.

Sporotrichosis co-infection with human immunodeficiency virus/acquired immunodeficiency syndrome.

Sporotrichosis is a subcutaneous mycosis caused by a dimorphic fungus belonging to the genus Sporothrix. This fungal infection can affect both humans and domestic animals, and in recent years, an increase in the geographic spread and prevalence of sporotrichosis has been observed globally. This systematic review aimed to examine the clinical-epidemiological and therapeutic aspects related to sporotrichosis co-infection with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). An extensive electronic search was conducted on databases including PubMed, Web of Science, Lilacs, Medline, Embase, Scopus and SciELO was performed to identify clinical cases of people living with HIV (PLWH) with sporotrichosis published until May 2023. As a result, we found that most co-infected patients were male, representing 71.76% (94/131) of cases. The most prevalent age group was 41-50 years, with a mean age of 36.98 years. The countries with the highest number of cases were Brazil (75.57%, 99/131) and the United States (16.03%, 21/131). The most frequent clinical presentation was systemic dissemination, accounting for 69.47% (91/131) of the cases, followed by cutaneous dissemination with 13% (17/131). The mean CD4+ cell count was 154.07 cells/µL, and most patients used amphotericin B with at least one azole, which represented 47.33% (62/131) of cases, followed by azole monotherapy in 17.56% (23/131) of cases. As for the outcome, 51.15% (67/131) of the patients remained alive, and 37.4% (49/131) died. Therefore, it was concluded that sporotrichosis in PLWH is a disease with a high prevalence in Brazil and may be associated with systemic clinical manifestations requiring longer periods of systemic antifungal therapy.

Case Report: Ocular Sporotrichosis-A Seven-Case Series.

Ocular infections associated with sporotrichosis can present four clinical manifestations: granulomatous conjunctivitis, dacryocystitis, Parinaud oculoglandular syndrome, and bulbar conjunctivitis. The incidence of ocular sporotrichosis related to zoonotic transmission has significantly increased in endemic regions and is a frequently misdiagnosed cause of granulomatous conjuntivitis. Therefore, we present a series of seven cases of eye injury by Sporothrix strains, including clinical forms, therapeutic approaches, and laboratory procedures to alert health professionals who provide care to these patients.

Sporothrix globosa melanin regulates autophagy via the TLR2 signaling pathway in THP-1 macrophages.

Melanin, an important virulence factor of pathogenic fungi, has been shown to suppress host immune responses in multiple ways. Autophagy is a vital cellular mechanism underlying the host's innate immunity against microbial infections. However, the potential influence of melanin on autophagy has not been explored. We investigated the effect of melanin on autophagy in macrophages, which play a key role in controlling Sporothrix spp. infection, as well as the mechanism of melanin interaction with Toll-like receptor (TLR)-induced pathways. Sporothrix globosa conidia (wild-type and melanin-deficient mutant strains) or yeast cells were co-cultured with THP-1 macrophages to demonstrate that, although S. globosa infection led to the activation of autophagy-related proteins and increased autophagic flux, S. globosa melanin suppressed macrophage autophagy. Incubation with S. globosa conidia also increased the expression levels of reactive oxygen species and multiple proinflammatory cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1ß and interferon-γ) in macrophages. These effects were attenuated as melanin presented. Furthermore, while S. globosa conidia significantly increased the expression of both TLR2 and TLR4 in macrophages, the knockdown of TLR2, but not TLR4, with small interfering RNA suppressed autophagy. Overall, this study revealed the novel immune defense ability of S. globosa melanin to inhibit macrophage functionality by resisting macrophage autophagy through the regulation of TLR2 expression.

Ocular Manifestations of Sporotrichosis in a Hyperendemic Region in Brazil: Description of a Series of 120 Cases.

PURPOSE: To describe 120 cases of ocular sporotrichosis. METHODS: Review of medical records of patients with culture-proven (from eye specimen) ocular sporotrichosis, in Rio de Janeiro, from 2007 to 2017. RESULTS: Women were more affected (61.7%) and median age was 24 years. The isolated ocular form was more frequent (75.8%). Fixed cutaneous sporotrichosis was the most commonly associated form (48.3%). Hypersensitivity reactions were observed in 10% of patients. Ocular involvement was unilateral in 98.3% of the cases, and the most frequent clinical presentation was granulomatous conjunctivitis (86.7%), followed by eyelid lesion (25%). Dacryocystitis represented 7.5% of the cases, predominantly in children (55.6%). Itraconazole was the first choice treatment (95.8%). Sequelae were observed in 23 patients (22.5%), and surgical treatment was required for most of them. CONCLUSION: Ocular sporotrichosis can be considered a characteristic form of the zoonotic transmission, with high morbidity. Delay in initiating specific treatment is likely to increase the risk of progression to more severe forms of the disease, and development of ocular sequelae.

Innate Immune Responses to Sporothrix schenckii: Recognition and Elimination.

Sporothrix schenckii (S. schenckii), a ubiquitous thermally dimorphic fungus, is the etiological agent of sporotrichosis, affecting immunocompromised and immunocompetent individuals. Despite current antifungal regimens, sporotrichosis results in prolonged treatment and significant mortality rates in the immunosuppressed population. The innate immune system forms the host's first and primary line of defense against S. schenckii, which has a bi-layered cell wall structure. Many components act as pathogen-associated molecular patterns (PAMPs) in pathogen-host interactions. PAMPs are recognized by pattern recognition receptors (PRRs) such as toll-like receptors, C-type lectin receptors, and complement receptors, triggering innate immune cells such as neutrophils, macrophages, and dendritic cells to phagocytize or produce mediators, contributing to S. schenckii elimination. The ultrastructure of S. schenckii and pathogen-host interactions, including PRRs and innate immune cells, are summarized in this review, promoting a better understanding of the innate immune response to S. schenckii and aiding in the development of protective and therapeutic strategies to combat sporotrichosis.

Are γ-terpinene, 1,8-cineole, p-coumaric acid, and quercetin active against wild-type and non-wild-type Sporothrix brasiliensis to itraconazole?

The emergence of itraconazole (ITZ)-resistant Sporothrix brasiliensis in feline and canine cases in southern Brazil has hampered the clinical cure of animal sporotrichosis, encouraging the search for therapeutic alternatives. The promising use of plants extracts from Lamiaceae family is known; however, there are no studies with its major compounds, as γ-terpinene (γTER), 1,8-cineole (1,8CIN), p-coumaric acid (pCOU), and quercetin (QUER). For the first time, we evaluated the antifungal, synergistic, cytotoxic activities and action mechanism of these compounds against S. brasiliensis. For this, 28 S. brasiliensis from cats (n = 24) and dogs (n = 4) and standard strains of S. brasiliensis and S. schenckii (n = 4) were tested by M38-A2 (CLSI), revealing non-wild-type (WT) isolates to ITZ on 54.2% (13/24) and 75% (03/04) of feline and canine isolates, respectively. Of the compounds, γTER stood out against all isolates (MIC/MFC 0.75 to > 3 mg/ml; MIC50 3 mg/ml). However, 1,8CIN, pCOU, and QUER showed little or no activity (MIC50 > 3 mg/ml). Thus, γTER was selected for checkerboard assay, whose combination with ITZ showed synergistic (WT isolates) and indifferent (non-WT isolates) interaction. For action mechanism (sorbitol protection and ergosterol effect), γTER acted in membrane by complexing with fungal ergosterol and at the cell wall level, showing two possible pathways as antifungal target. Finally, cytotoxicity (MTT assay) showed that γTER was the safest compound on MDBK cells, even at a concentration of 3 mg/ml (90.16%). Our findings support that γTER is a potent antifungal candidate for the control of sporotrichosis, including against non-WT S. brasiliensis.

Esporotricosis en Argentina: análisis clínico y epidemiológico / Sporotrichosis in Argentina: clinical and epidemiological analysis

Introducción. La esporotricosis es una micosis de implantación causada por Sporothrix spp. Este se encuentra distribuido mundialmente y se puede encontrar en la vegetación y en el suelo. La ruta más frecuente de adquisición de la infección es por traumatismos con elementos contaminados con propágulos del hongo. Los gatos domésticos son los animales más afectados y pueden transmitirla a los humanos, por lo que es considerada una zoonosis. Las formas clínicas incluyen: la linfangítica nodular, la cutánea fija, la pulmonar (poco habitual) y la diseminada (excepcional). Objetivo. Analizar la epidemiología de la esporotricosis en Argentina entre los años 2010 y 2022. Describir la presentación clínica, los métodos de diagnóstico y el tratamiento de los casos diagnosticados en este período. Conocer los genotipos circulantes y observar su relación con el lugar geográfico de adquisición de la infección. Materiales y métodos. Se llevó a cabo un estudio analítico, retrospectivo y observacional, en el que se analizaron las historias clínicas de los pacientes con esporotricosis de 12 instituciones de salud de Argentina, entre los años 2010 y 2022. Resultados. Se presentan 54 casos en los que la forma clínica más frecuente fue la linfangítica nodular y el tratamiento de elección fue el itraconazol. En todos los casos se realizó diagnóstico convencional. El cultivo de las muestras clínicas resultó más sensible que el examen directo, ya que permitió el desarrollo de Sporothrix spp. en los 54 casos. En 22 casos se hizo identificación molecular y Sporothrix schenkii sensu stricto fue la especie más frecuentemente aislada. Conclusiones. Este estudio permitió conocer la epidemiología de esta micosis en Argentina, así como la disponibilidad de métodos diagnósticos y el tratamiento de elección.

Introduction. Sporotrichosis is an implantation mycosis caused by Sporothrix spp. It is distributed worldwide and can be found in vegetation and soil. The most frequent route of infection is by trauma with elements contaminated with fungal propagules. Since domestic cats are the most affected animals and can transmit this infection to humans, sporotrichosis is considered a zoonosis. Clinical presentations include nodular lymphangitis, fixed cutaneous, pulmonary (rare), and disseminated (exceptional). Objective. To analyze the epidemiology of sporotrichosis in Argentina during 2010 and 2022. To describe the clinical presentation, diagnostic methods, and treatment of cases diagnosed during this period. To know the circulating genotypes and to observe possible associations with the geographic location where the infection was acquired. Materials and methods. Analytical, retrospective, and observational study. We analyzed the medical records of patients with sporotrichosis from 12 health institutions in Argentina, between 2010 and 2022. Results. We present 54 cases in which the most frequent clinical form was nodular lymphangitis, and the treatment of choice was itraconazole. Conventional diagnosis was made in all cases. Culture of clinical samples was more sensitive than direct examination because it allowed the isolation of Sporothrix spp. in all 54 cases. Molecular identification was performed in 22 cases, with Sporothrix schenkii sensu stricto being the most frequently isolated species. Conclusions. This study allowed to know the epidemiology of this mycosis in Argentina, as well as the availability of diagnostic methods and the treatment of choice.

Phenotypic and genotypic characterization of Colombian clinical isolates of Sporothrix spp / Caracterización fenotípica y genotípica de aislamientos clínicos colombianos de Sporothrix spp

Introduction. For over a century, Sporothrix schenckii was considered the sole species responsible for sporotrichosis. In 2007, scientific community confirmed the disease could be caused by various Sporothrix species. These species differed in their virulence factors and their antifungal sensitivity. Objective. This study aims to characterize 42 Colombian clinical isolates of Sporothrix spp. phenotypically and genotypically. Materials and methods. Forty-two clinical isolates were characterized using phenotypic methods. It involved various culture media to determine their growth range at different temperatures and to assess the type and distribution of pigment and colony texture. Microscopic morphology was evaluated through microcultures, as well as the conidia diameter, type of sporulation, and morphology. Additionally, the assimilation of carbohydrates was selected as a physiological trait for species identification. Genotyping of 40 isolates was performed through partial amplification of the calmodulin gene, followed by sequence analysis. Results. Molecular studies enabled the identification of 32 isolates of S. schenckii and 8 isolates of S. globosa. The combination of phenotypic and genotypic methods eased these species characterizations and the recognition keys development based on parameters such as growth diameter at 25 and 30 °C, colony texture (membranous or velvety) on potato dextrose agar, and microscopic morphology with predominance of pigmented triangular, elongated oval globose, or subglobose conidia. Conclusions. Confirmation of the phenotypic characteristics and molecular analysis is crucial for identifying Sporothrix species and determining adequate treatment. This study represents the first phenotypical and genotypical characterization of clinical isolates of Sporothrix spp. reported in Colombia.

Introducción. Por más de un siglo se creyó que Sporothrix schenckii era la única especie responsable de la esporotricosis. Sin embargo, en el 2007, se consideró que podría ser causada por diferentes especies de Sporothrix, que difieren en sus factores de virulencia y su sensibilidad a los antifúngicos. Objetivo. Caracterizar fenotípica y genotípicamente 42 aislamientos clínicos colombianos de Sporothrix spp. Materiales y métodos. Se caracterizaron 42 aislamientos clínicos mediante métodos fenotípicos. Se usaron varios medios de cultivo para determinar el rango de crecimiento a diferentes temperaturas, el tipo y la distribución del pigmento, y la textura de las colonias. Se evaluó la morfología microscópica por microcultivos mediante la determinación del diámetro, el tipo de esporulación y la morfología de las conidias. La asimilación de carbohidratos se usó como una característica fisiológica para identificar las especies. La genotipificación de los 40 aislamientos se llevó a cabo mediante la amplificación parcial del gen que codifica para la calmodulina y se confirmó por secuenciación. Resultados. Mediante estudios moleculares, se identificaron 32 aislamientos de S. schenckii y ocho de S. globosa. La combinación de métodos fenotípicos y genotípicos permitió caracterizar las especies y construir claves para su reconocimiento, con base en parámetros como el diámetro de crecimiento a 25 y 30 °C, la textura de las colonias (membranosa, aterciopelada) en agar papa dextrosa y la morfología microscópica con predominio de conidias (triangulares pigmentadas, ovales globosas elongadas, subglobosas). Conclusiones. La caracterización fenotípica y los análisis moleculares son necesarios para identificar las especies de Sporothrix y, de esta forma, elegir el tratamiento indicado. Esta es la primera caracterización fenotípica y genotípica reportada de aislamientos clínicos colombianos de Sporothrix spp.

Spread of Sporothrix spp. through respiratory droplets from infected cats: A potential route of transmission.

Cases of cat-transmitted sporotrichosis in Brazil have increased in recent years. We collected respiratory secretions expelled while sneezing from 28 cats diagnosed with sporotrichosis. We identified the presence of Sporothrix spp. in respiratory droplets expelled in the sneeze of infected cats. The results raise concerns about a new transmission route for cat-transmitted sporotrichosis. Physicians who diagnose and treat human cases of sporotrichosis should be aware of this potential new transmission method to improve clinical suspicion. Approximately half of patients with granulomatous conjunctival sporotrichosis did not report experiencing traumatic injury from cats.

Cat-transmitted sporotrichosis is a zoonosis in geographic expansion from Brazil to other Latin American countries and is considered a public health problem. Data suggest that transmission can occur through the sneeze of an infected cat. The One Health approach is necessary to control the disease.

An unsuspected and unusual case of zoonotic sporotrichosis.

Sporotrichosis is an infection caused by a thermally dimorphic fungus, Sporothrix schenckii which is commonly reported in the tropics and subtropics. Infection usually occurs as a consequence of traumatic inoculation into the skin. A previously healthy 33-year-old Malay woman presented with a scratch wound over the lateral aspect of her left thigh for 2 months after being scratched by her pet cat. Inspection of the wound revealed a granulomatous plaque measuring 3cm x 2cm with hyperkeratotic scales, fissures and multiple blackish pigments. There was a tender, palpable left inguinal lymph node measuring 1cm x 1cm but the overlying skin looked normal. She was prescribed two courses of antibiotics empirically, without any clinical improvement seen. During follow up and further history taking, the patient informed that her pet cat was diagnosed with sporotrichosis a month before the scratching incident took place, but she claimed that her pet cat had been treated and was cured. She was then empirically started with oral itraconazole 200mg twice a day for two months. Histopathological examination of a skin biopsy showed acute on chronic suppurative granulomatous inflammation but was negative for any fungal elements. However, culture of the skin biopsy isolated Sporothrix schenckii. A final diagnosis of localised cutaneous sporotrichosis was made and the oral itraconazole was continued for another two months. The wound improved dramatically since itraconazole started.

Citromycin Isolated from the Antarctic Marine-Derived Fungi, Sporothrix sp., Inhibits Ovarian Cancer Cell Invasion via Suppression of ERK Signaling.

Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial-mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.

Sporothrix schenckii regulates macrophage inflammatory responses via the c-JUN-induced Dab2 transcription.

Macrophages, which serve as a bridge between innate and adaptive immunity, play an important role in sporotrichosis. Sporothrix schenckii infections can produce immune responses such as macrophage polarization and inflammatory factor secretion. In the early stages of inflammation, the expression of DAB2 in macrophages is increased, which controls the secretion of inflammatory factors and affects the polarization of macrophages. However, the expressions and mechanisms of DAB2 in sporotrichosis are not clear. In this study, we examined the expression of DAB2 and its regulation of inflammatory factors under conditions of Sporothrix schenckii infection. Our results indicated that the Sporothrix schenckii infection increased the expression of DAB2 and revealed a mixed M1/M2-like type of gene expression in BMDMs with the inhibited Il-6, Il1-ß and Arg-1 and induced Tnf-α, Il-10 and Mgl-1. The deficiency of Dab2 gene suspended the changes of cytokines. In addition, JNK activity in BMDMs was inhibited by Sporothrix schenckii infection, leading to an increase in c-JUN. We also identified c-JUN as a transcription factor for Dab2 through chromatin immunoprecipitation and luciferase reporter assays. In an in vivo mouse model, sporotrichosis-induced skin lesions were accompanied with an upregulation of c-JUN and inhibition of JNK activity, which were in accord with findings from in vitro experiments. Taken together, these findings indicate that in the early stages of Sporothrix schenckii infection there is a promotion of DAB2 expression through the JNK/c-JUN pathway, effects that can then control the expression of inflammatory factors.