RARE DISEASE
Sporotrichosis
Sporotrichosis
Sporotrichosis
Drug discovery
1
drug
With orphan designation
Overview
Sporotrichosis is a fungal infection caused by Sporothrix species, primarily S. schenckii and S. brasiliensis. Transmission occurs through cutaneous inoculation (via plant materials or cat scratches/bites) or spore inhalation. Cutaneous presentations include painless nodules progressing to ulcerative lesions, while disseminated forms (pulmonary, osteoarticular, CNS) occur in immunocompromised hosts. Diagnosis relies on culture, histopathology, or PCR [1][3][6].
Burden
• South America accounts for >87% of global cases, driven by S. brasiliensis epidemics in Brazil [2][9][19]
• Prolonged treatment (6-12+ months) increases healthcare costs and medication non-adherence [3][10][19]
• Occupational disability in agrarian communities; stigma from disfiguring lesions impacts mental health [4][9][19]
Clinical note: Cat-associated transmission requires concurrent veterinary management to prevent reinfection [5][12].
Therapies
• First-line: Oral itraconazole (200-400 mg/day for 3-6 months) for cutaneous/lymphocutaneous forms [3][6][15]
• Severe/systemic: Liposomal amphotericin B (3-5 mg/kg/day), transitioning to itraconazole [3][6][15]
• Resource-limited settings: Potassium iodide (SSKI) or terbinafine as alternatives [8][15]
Categories: rare infectious diseases
Research Papers
724 drug discovery papers about Sporotrichosis, with 25 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
724 drug discovery papers about Sporotrichosis, with 25 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Molecular and Epidemiological Surveillance of Sporothrix spp. in Cats and Dogs from Southern Brazil.
Sporotrichosis, a subcutaneous mycosis caused by Sporothrix spp., has emerged as a major zoonotic disease in Brazil, primarily driven by Sporothrix brasiliensis. The southern state of Rio Grande do Sul exhibits distinctive ecological and climatic conditions that may shape the persistence and distribution of this pathogen in this region. This study conducted molecular and epidemiological surveillance of feline and canine sporotrichosis in southern Rio Grande do Sul, Brazil. A total of 100 isolates from the culture collection of the Veterinary Mycology Laboratory at the Federal University of Pelotas (UFPel) were analyzed by PCR targeting the calmodulin (CAL) gene for species identification. Fourteen representative isolates were sequenced and subjected to phylogenetic analysis using the Maximum Likelihood method, including reference sequences from Brazil, Paraguay, and Argentina. Epidemiological and clinical variables, including host species, sex, lesion site, and morphology, were evaluated to characterize the epidemiological and clinical profiles of sporotrichosis in the study region. S. brasiliensis and S. schenckii were identified in 97% and 3% of the isolates, respectively. The CAL-based phylogeny confirmed the monophyly of S. brasiliensis and revealed low intraspecific variability with regional clustering among southern Brazilian isolates. When interpreted within the Southern Cone context, the topology indicated a close genetic affinity between isolates from Rio Grande do Sul and reference sequences from Argentina and Paraguay. These findings confirm the territorial expansion of S. brasiliensis across southern Brazil and emphasize the importance of molecular surveillance for detecting and tracking the circulating lineages. Continuous regional monitoring is crucial for strengthening One Health strategies and mitigating the zoonotic spread of sporotrichosis in the Southern Cone.
2026-09-17 | Human sporotrichosis in the Amazon: an emerging zoonosis and its clinical-epidemiological challenges.
The number of sporotrichosis cases in Brazil has been continuously increasing, primarily due to zoonotic transmission in urban areas. This study aimed to analyze the occurrence of human sporotrichosis in a reference center in the Amazon region. This case series study analyzed the medical records of patients diagnosed with sporotrichosis at a dermatology reference service in Northern Brazil. Most patients presented with the localized cutaneous form. Diagnosis was confirmed using clinical and epidemiological criteria, histopathology, and/or culture. Diagnostic suspicion, especially in endemic areas, and early treatment are essential to reduce morbidity, sequelae, and adverse outcomes.
2026-08-19 | Towards standardized antifungal susceptibility testing for Sporothrix brasiliensis.
Sporotrichosis caused by Sporothrix brasiliensis is increasingly reported in South America. Infections in humans are mostly due to zoonotic transmission by cats. For both hosts, itraconazole is the drug of choice despite long treatment duration. Resistance surveillance is warranted, but protocols for antifungal susceptibility testing (AFST) are not always harmonized between laboratories largely due to Sporothrix species being thermally dimorphic and the absence of well-defined consensus methodologies to address how to deal with yeast/mould phases. To standardize susceptibility testing methodology, we propose to modify the current Clinical Laboratory and Standards Institute (CLSI) M38 broth microdilution methodology with S. brasiliensis culture for 7 days at 30°C (rather than 35°C) on potato dextrose agar (PDA), followed by microscopic confirmation of pure mycelial phase. Incubation temperature would also be modified to 30°C for 72 hours. By following this standardized method for at least itraconazole, terbinafine and amphotericin B, S. brasiliensis non-wild-type isolates and correlations with clinical outcomes can be properly investigated. The proposed method is a consensus-oriented interim approach rather than a fully validated standard.
2026-08-18 | Antimicrobial resistance in Staphylococcus spp. isolated from sporotrichosis-affected cats in Brazil: Detection of MRSP and MRSA.
Recently, Brazil has experienced a zoonotic emergence of sporotrichosis. The associated cutaneous lesions are often extensive and slow to heal, thereby providing a gateway for opportunistic bacteria belonging to the normal skin microbiota. Among these, Staphylococcus spp. are of particular concern due to their high prevalence and notable levels of antimicrobial resistance. The objective of this study was to identify and characterize Staphylococcus spp. isolated from the cutaneous wounds of domestic cats undergoing treatment for sporotrichosis and exhibiting clinical signs of secondary bacterial infection. A total of 233 samples from 203 cats were analyzed. Staphylococcus spp. was isolated from 156 samples (67%), with S. aureus (42.3%) and S. felis (25.6%) being the most prevalent. Antimicrobial susceptibility testing revealed high levels of resistance to penicillin (51.9%), erythromycin (28.8%), and clindamycin (19.2%). In contrast, most isolates were susceptible to chloramphenicol (98%), ciprofloxacin (96.7%), and nitrofurantoin (93%). Multidrug-resistant strains were identified in 24% (38/156) of the isolates. Overall, 12 isolates (7.7%) were classified as methicillin-resistant staphylococci, including four methicillin-resistant S. pseudintermedius (MRSP) and one methicillin-resistant S. aureus (MRSA). To investigate the genetic profiles and epidemiological relationships of these isolates, all the MRSP and MRSA strains were subjected to whole-genome sequencing. Among the MRSP isolates, four sequence types (STs) were identified, including ST551, the founder of clonal complex (CC)551, which is commonly associated with infection in dogs. The MRSA isolate belonged to ST1176, a member of CC5, which is a globally prevalent lineage and is frequently associated with nosocomial infections in humans. This study demonstrates that Staphylococcus species, including methicillin-resistant isolates, are frequently present in the wounds of sporotrichosis-infected cats exhibiting clinical signs of secondary bacterial infection. The detection of MRSA and MRSP in a cat highlights an additional public health concern associated with feline sporotrichosis and further reinforces the growing concern regarding antimicrobial resistance in companion animals.
2026-08-12 | Sporotrichosis-induced oxidative imbalance in liver and kidneys of rats infected with Sporothrix brasiliensis: renoprotective effects of farnesol.
Sporothrix brasiliensis is the most virulent species of the genus Sporothrix. Oxidative stress is a key defense mechanism to eliminate this pathogen through generation of reactive oxygen species (ROS). However, S. brasiliensis has developed mechanisms to counteract this response, contributing to its persistence in the host. This paradoxically leads to excessive ROS production in host tissues, inducing oxidative stress. Bearing this in mind, the use of plant-based natural products such as farnesol (terpene) is considered an approach to attenuate oxidative stress, as this compound is known to possess radical scavenging properties. The aim of this study was to determine whether oral administration of farnesol (100 mg/kg) might prevent or attenuate S. brasiliensis-induced in rat renal and hepatic oxidative stress. Renal ROS, thiobarbituric acid reactive substance (TBARS) levels, and both hepatic and renal glutathione S-transferase (GST) activity were significantly higher in infected (group C) compared to uninfected animals (group A), while catalase (CAT) activity was significantly lower. No significant differences were observed between groups regarding hepatic ROS and TBARS levels, as well as superoxide dismutase activity. Farnesol administered to infected animals (group D) attenuated the rise in renal ROS and TBARS levels, as well as GST activity compared to group C. In conclusion, data demonstrated that S. brasiliensis infection induced renal oxidative stress mediated by elevation in ROS levels, initiating membrane lipid damage and diminished CAT activity. The protective effects of farnesol may be attributed to a synergistic effect of its ROS-scavenging ability, diminished lipid damage, and enhanced GST activity.
proteins
2026-06-22 | Antifungal and Therapeutic Evaluation of l- and d‑Enantiomers of a Plant Defensin-Inspired Peptide against Sporothrix schenckii and Sporothrix brasiliensis.
Sporotrichosis is an emerging subcutaneous mycosis and an important public and veterinary health concern in Brazil. The ongoing expansion of feline-associated transmission, particularly involving Sporothrix brasiliensis, has reinforced the need for new antifungal strategies. In this study, we evaluated the antifungal potential of the bioinspired peptide L-CaDef2.1G27‑K44 (L-CDF-GK) and its enantiomer D-CaDef2.1G27‑K44 (D-CDF-GK), derived from a defensin identified in Capsicum annuum fruits. Antifungal activity was assessed through in vitro and in vivo assays, together with the investigation of possible mechanisms of action. The analyses included fungal growth inhibition, cytoplasmic membrane permeabilization, oxidative stress induction, mitochondrial depolarization, and erythrocyte cytotoxicity. In vivo, Galleria mellonella larvae were used to evaluate therapeutic potential by survival analysis, melanization quantification, and hemocyte density determination. Both peptides exhibited significant dose-dependent antifungal activity against Sporothrix schenckii and S. brasiliensis. The L-isoform completely inhibited the growth of both species at 100 μM, whereas the D-isoform inhibited 90% of S. schenckii growth and 70% of S. brasiliensis growth. IC50 analysis and functional assays performed with S. schenckii showed that both peptides induced membrane permeabilization, increased reactive oxygen species production, and loss of mitochondrial membrane potential. In the G. mellonella infection model, lethal dose determination indicated greater virulence of S. brasiliensis. Both peptides showed low toxicity and significantly improved the survival of larvae infected with S. schenckii, with minimal activation of cellular and humoral immune responses. Together, these findings support the potential of CDF-GK-derived peptides as promising candidates for the development of new antifungal strategies against sporotrichosis.
2026-01-01 | Sporothrix schenckii Peptidorhamnomannan-Associated Protein 2 (Pap2) Is Involved in Adhesion and Virulence.
The Sporothrix schenckii cell wall has been widely studied to understand its role in pathogenesis and the infection process. Previously, a component of the cell wall, the peptidorhamnomannan (PRM), was analyzed, and some proteins with unknown function were identified. Among them, the protein encoded by the SPSK_06559 gene stood out for its high abundance within PRM. In this work, in silico analyses were performed to predict the adhesive properties of the SPSK_06559 protein (renamed as Pap2) to extracellular matrix (ECM) components, such as fibrinogen, fibronectin, and type-I and type-II collagen. Subsequently, a recombinant Pap2 (rPap2) version was generated to obtain experimental evidence of its adhesive properties to ECM components. Finally, the role of Pap2 in pathogenesis was assessed in Galleria mellonella larvae. Bioinformatic analyses consistently suggested that Pap2 possesses adhesive properties. Prediction was experimental validated: rPap2 showed strong adhesion to ECM components. Immunization with rPap2 conferred significant protection to G. mellonella larvae against a lethal dose of S. schenckii. Furthermore, preincubation of fungal cells with anti-rPap2 antibodies drastically reduced their ability to kill the larvae. These findings demonstrate that the SPSK_06559 protein (Pap2) participates in the initial adhesion to host tissues. Induction of a protective response through immune priming with rPap2 suggest that Pap2 is a promising immunogenic antigen. Reduction of lethality upon blocking Pap2 confirms its essential role in pathogenesis, positioning it as a potential target for the development of new therapies and vaccines against sporotrichosis.
2025-12-04 | The Cbp1 protein is a peptidorhamnomannan adhesin that contributes to the Sporothrix schenckii virulence.
Sporothrix schenckii pathogenesis has been extensively studied to date, but several proteins of unknown function remain to be assigned to the infectious process. Previously, proteomic data showed that one protein was highly abundant (SPSK_02764) in cell wall peptidorhamnomannan, but no obvious homologs or sequence features hinted at the activity or function of this protein. In this work, in vitro analysis showed that this protein is highly glycosylated and is an adhesin with specificity for type-I and type-II collagen, renaming this protein as Collagen Binding Protein 1 or Cbp1. Yeast-like cells preincubated with anti-SPSK_02764 antibody reduced the ability to kill Galleria mellonella larvae and to induce immune effectors, suggesting a role for this protein in S. schenckii pathogenesis. Bioinformatic analysis suggested that the protein may be a moonlighting protein that is broadly present in Ascomycota and is sequence and structurally conserved. The findings shown here suggest that Cbp1 is another component of the S. schenckii cell wall and participates in host collagen binding, adding a new component to the pathogenesis toolbox of this organism.
2025-11-22 | Immune genes CD247 STAT1 and LCK mediate host-pathogen interactions in sporotrichosis.
Sporotrichosis is a chronic subcutaneous infection caused by the Sporothrix complex, a dimorphic fungus that exhibits significant clinical heterogeneity. However, the molecular targets and underlying mechanisms of Sporothrix globosa infection remain unclear. Therefore, in this study, we aimed to integrate whole-transcriptome sequencing analysis of skin lesion tissues from patients with sporotrichosis and healthy controls. In addition, differential gene expression screening, protein-protein interaction network construction, and functional enrichment analysis. We systematically identified the key immune-related genes, Cluster of Differentiation 247 (CD247), Signal Transducer and Activator of Transcription 1 (STAT1), and Lymphocyte-Specific Tyrosine Kinase (LCK), which are majorly upregulated during infections. The high expression of these genes in the disease group was consistently validated by western blot, quantitative polymerase chain reaction, and immunohistochemistry. Mechanistic analysis revealed the contribution of these genes to sporotrichosis-dysregulated immune response. This occurs by causing excessive activation of the interferon signaling pathway, lymphocyte overactivation, and the JAK-STAT signaling pathway, which leads to the host immune imbalance. This suggests their central role in immune evasion and overactivation during sporotrichosis. In this novel study, we revealed the pathological regulatory role of the CD247-STAT1-LCK molecular network in sporotrichosis, which provided novel insights into fungal-host interactions and identified potential therapeutic targets for immune-modulating antifungal treatments.
2025-11-14 | An anti-adhesive peptide found in extracellular vesicles from Sporothrix brasiliensis and Sporothrix schenckii.
Sporothrix brasiliensis and Sporothrix schenckii are major causative agents of sporotrichosis, a neglected fungal disease with growing public health relevance. These pathogens release extracellular vesicles (EVs) that contribute to host-pathogen interactions, yet their small molecule content remains unexplored. Here, we isolated EVs from both species following growth on solid medium and characterized them using nanoparticle tracking analysis, transmission electron microscopy, proteomics, and untargeted metabolomics. While EVs from each species contained distinct sets of proteins, a subset of conserved components and metabolites was identified, including the dipeptidyl peptidase IV (DPP4) inhibitor isoleucine-proline-isoleucine (IPI), previously described as a protective EV component in Cryptococcus. Functional assays demonstrated that both IPI and an anti-DPP4 antibody significantly impaired fungal adhesion to type I collagen. These findings reveal new layers of molecular complexity in the EVs of Sporothrix spp., highlight the presence of functionally conserved small molecules, and suggest a role for EV-derived peptides in modulating fungal surface interactions with host structures.
antibodies
2025-02-07 | Management of sporotrichosis in patients with inflammatory bowel disease using biological therapy (antitumor necrosis factor).
Antitumor necrosis factor (TNF)-alpha (TNFa) drugs are crucial for treating inflammatory bowel disease (IBD) but may increase opportunistic infection risk. Among such infections, sporotrichosis is a chronic granulomatous disease caused by saprophytic dimorphic fungi of the genus Sporothrix, which occurs worldwide. To date, there have been no reports of sporotrichosis in immunosuppressed IBD patients. The main objectives are to discuss clinical, diagnostic, and therapeutic aspects of sporotrichosis in IBD patients on anti-TNF therapy. We describe three patients with IBD on TNFa therapy who contracted cutaneous-disseminated and extracutaneous sporotrichosis and discuss strategies for managing sporotrichosis and IBD therapy in this scenario. The first case is a patient with ulcerative colitis with mild lymphocutaneous sporotrichosis who did not require discontinuation of anti-TNF agents and methotrexate. The other two patients had rapidly progressive extensive lymphocutaneous disease and disseminated sporotrichosis. These patients required hospitalization, a temporary discontinuation of their biological therapy, and a subsequent switch to vedolizumab. In all cases, the sporotrichosis was successfully treated and none of them experienced serious complications. Sporotrichosis should be considered in anti-TNF IBD patients with opportunistic infections. Early diagnosis, infection treatment, education of cat owners, and population control programs are necessary.
2023-03-30 | Inflammation and epigenetics of sporotrichosis disease.
Sporotrichosis, a fungal disease, is caused by exposure to soil that harbors Sporothrix schenckii or through inhalation of fungal spores. Skin is the most frequently exposed organ making sporotrichosis a primarily dermal disease. Many described reports in the literature suggest a connection of sporotrichosis with cutaneous squamous cell carcinoma with some connection between initial sporotrichosis diagnosis and treatment followed by development of cutaneous squamous cell carcinoma at the very site. Conversely, there is also evidence for sporotrichosis subsequent to skin cancer diagnosis, even after cancer chemotherapy, which points towards weakening of immune response by cancer chemotherapy leading to attack and infection by Sporothrix schenckii. We also propose and focus on inflammation as the connection between sporotrichosis, cancer and even the metastatic spread of cancer. Inflammation-associated IL-6, IFN-γ, natural killer cells and M2-macrophages possibly mechanistically link sporotrichosis with cancer, particularly cutaneous squamous cell carcinoma. These inflammation related factors/cells are regulated epigenetically raising the possibility of epigenetic regulation of sporotrichosis, which has not been described yet in the available literature. Clinical management of inflammation may thus be effective strategy not just against sporotrichosis but also the related onset of cutaneous squamous cell carcinoma and possibly its metastasis to lymph nodes.
2022-08-01 | Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. Schenckii
Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) from S. brasiliensis has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host's immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. We demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.
2022-01-11 | Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. schenckii
Abstract Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix , with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) of Sporothrix spp . is a pathogen associated molecular pattern (PAMP). Interestingly, S. brasiliensis PRM has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host’s immune response and may explain the severity of sporotrichosis caused by S. brasiliensis . Here we demonstrate that S. brasiliensis yeasts and its PRM ( S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis . The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.
2021-11-04 | Transient Foxp3(+) regulatory T-cell depletion enhances protective Th1/Th17 immune response in murine sporotrichosis caused by Sporothrix schenckii.
The role of regulatory T cells (Tregs) on protective immunity in fungal infections, is controversial. Sporotrichosis is an emerging and worldwide-distributed subcutaneous mycosis caused by various related thermodimorphic fungi of the genus Sporothrix. Previously, we showed an elevated percent of Tregs around 21 days post-infection (dpi) in C57BL/6 mice infected with either Sporothrix schenckii or Sporothrix brasiliensis, but the effect of these cells in the ongoing infection was not evaluated. Here, we aim to characterize the role of Foxp3+ Tregs in a subcutaneous S. schenckii infection model. The flow cytometric analyses showed that S. schenckii infection elicited an expansion of a splenic CD4+Foxp3+ population, including a subset of Helioslow+ after ex vivo stimulation with S. schenckii-heat killed yeast. Depletion of Tregs in DEREG mice revealed a reduction of fungal burden in the skin and systemically in liver and kidneys, associated with enhanced Th1 and Th17 responses. Altogether, our results reveal for the first time that Tregs depletion in ongoing S. schenckii infection improves the protective antifungal immunity and these data suggest that Tregs modulation could be explored as a potential therapeutic strategy in sporotrichosis.
vaccines
2026-09-24 | SgtrCypB Formulated with Freund's Adjuvant Confers Protective Immunity Against S. globosa and Partial Cross-Protection Against S. schenckii Infections in Mice.
Sporothrix globosa is the predominant cause of sporotrichosis in China, highlighting the need for effective vaccine strategies. Cyclophilins from pathogenic microorganisms have emerged as potential vaccine antigens. We previously generated a high-yield, high-purity recombinant truncated S. globosa cyclophilin B protein (SgtrCypB) retaining its functional domain. Here, BALB/c mice were immunized subcutaneously with SgtrCypB alone or formulated with Freund's adjuvant to evaluate immunogenicity. Only the adjuvant-formulated vaccine induced a high antibody titer (1:51,200). Then, the infection-challenge experiments compared the SgtrCypB formulated with Freund's adjuvant and PBS formulated with Freund's adjuvant groups. Following challenge, SgtrCypB plus adjuvant reduced cutaneous lesion size (0.6 vs. 1.0 cm at week 1) without significantly affecting ulcer incidence. In systemic S. globosa infection, vaccination increased survival to 90% versus 40% in controls and reduced organ fungal burdens. Partial cross-protection was observed against S. schenckii, with 60% versus 20% survival and lower fungal burdens in the kidneys and lungs. Protection against C. albicans was minimal. These findings identify SgtrCypB as a promising protective antigen against S. globosa and S. schenckii and support further evaluation with clinically applicable adjuvants.
2025-12-22 | Sporothrix brasiliensis and cats: understanding the disease and the promising potential of veterinary antifungal vaccination for a healthier future of both humans and animals
Abstract Sporotrichosis is a subcutaneous fungal infection caused by species of the Sporothrix genus that affects both humans and animals. Sporothrix brasiliensis is a dimorphic fungus that exists in a mycelial and conidial phase in nature and is a yeast in its parasitic stage or when cultured at 37°C. Since its first identification in animals in 1907, the disease has become a significant concern, especially given the increasing number of cases in cats, particularly in urban areas. This has contributed to an increase in zoonotic transmission and the current epidemic of sporotrichosis in Brazil. Virulent strains of S. brasiliensis , combined with the increased susceptibility of felines, have exacerbated the public health challenge posed by sporotrichosis. As with other infectious diseases, immunomodulation presents a promising strategy for the prevention, treatment, and control of sporotrichosis in animals, potentially reducing zoonotic transmission. This review examines the role of cats in the transmission of this disease, the interactions between Sporothrix species and the host immune system, and the progress in the development of antifungal vaccines. We also highlight ongoing research into vaccine strategies. Ultimately, our goal is to encourage further dialog on effective approaches to control the rapid spread of zoonotic sporotrichosis. Graphical Abstract Sporothrix brasiliensis drives a growing sporotrichosis epidemic in Brazil, with domestic cats serving as the key zoonotic reservoir. This review examines the feline-driven transmission cycle, host‒pathogen immune interactions, and current progress in vaccine development. Immunomodulation through feline vaccination has emerged as a crucial strategy for breaking the transmission chain and controlling this public health threat.
2025-01-27 | Sporothrix brasiliensis Gp70 is a cell wall protein required for adhesion, proper interaction with innate immune cells, and virulence.
Sporothrix brasiliensis is one of the leading etiological agents of sporotrichosis, a cutaneous and subcutaneous mycosis worldwide distributed. This organism has been recently associated with epidemic outbreaks in Brazil. Despite the medical relevance of this species, little is known about its virulence factors, and most of the information on this subject is extrapolated from Sporothrix schenckii. Here, we generated S. brasiliensis mutants, where GP70 was silenced. In S. schenckii, this gene encodes a glycoprotein with adhesive properties required for virulence. The S. brasiliensis GP70 silencing led to an abnormal cellular phenotype, with smaller, round yeast-like cells that aggregate. Cell aggregation was disrupted with glucanase, suggesting this phenotype is linked to changes in the cell wall. The cell wall characterization confirmed changes in the structural polysaccharide β-1,3-glucan, which increased in quantity and exposure at the cell surface. This was accompanied by a reduction in protein content and N-linked glycans. Mutant strains with high GP70-silencing levels showed minimal levels of 3-carboxy-cis,cis-muconate cyclase activity, this glycoprotein's predicted enzyme function, and decreased ability to bind laminin and fibronectin. These phenotypical changes coincided with abnormal interaction with human peripheral blood mononuclear cells, where production of IL-1β, IL-17, and IL-22 was reduced and the strong dependence on cytokine stimulation via mannose receptor was lost. Phagocytosis by monocyte-derived macrophages was increased and virulence attenuated in a Galleria mellonella larvae. In conclusion, Gp70 is an abundant cell wall glycoprotein in S. brasiliensis that contributes to virulence and proper interaction with innate immnune cells.
2022-10-07 | Recombinant phage displaying ToAP2D peptide with antifungal activity against Sporothrix globosa
We designed and synthesized recombinant phage nanofibers displaying ToAP2D peptide and investigated their antifungal effect on Sporothrix and the corresponding mechanism. Antimicrobial peptide, ToAP2D, was used as the template. The effect of synthesized recombinant phages on the immune function of CD4+ T lymphocytes in mice was tested using an enzyme-linked immunosorbent assay. The therapeutic effect and safety of recombinant phage administration on Sporothrix-infected BALB/c mice were evaluated based on survival analysis, histopathological changes, and renal and liver functions. The successfully prepared recombinant phage displaying ToAP2D peptides significantly inhibited Sporothrix growth. According to the scanning electron microscopy results, the recombinant phage caused shrinkage and rupture of Sporothrix globosa, leading to leakage of the contents. The Hoechst/propidium iodide double staining test indicated that the recombinant phage could induce cell apoptosis of Sporothrix globosa. The apoptotic pathway might be due to the accumulation of reactive oxygen species in large quantities in cells, activating caspase dependence; this reduced inflammation, prolonged the survival time, and enhanced levels of IFN-γ and IL-17 in mice. We believe that recombinant phage inhibits Sporothrix growth by adjusting the immune response of mice, inducing Sporothrix apoptosis and improving animal survival. This study offers a new approach to preparing antimicrobial peptides.
2022-05-17 | A Sporothrix spp. enolase derived multi-epitope vaccine confers protective response in BALB/c mice challenged with Sporothrix brasiliensis.
Sporotrichosis is a cosmopolitan mycosis caused by pathogenic species of Sporothrix genus, that in Brazil is often acquired by zoonotic transmission involved infected cats with S. brasiliensis. Previous studies showed that the Sporothrix spp. recombinant enolase (rSsEno), a multifunctional protein with immunogenic properties, could be a promising target for vaccination against sporotrichosis in cats. Nevertheless, the considerable sequence identity (62%) of SsEno with its feline counterpart is a great concern. Here, we report the identification in silico, chemical synthesis and biological validation of six peptides of SsEno with low sequence identity to its cat orthologue. All synthesized peptides exhibit B-cell epitopes on the molecular surface of SsEno and proved to be highly reactive with the serum of infected mice with S. brasiliensis and sera of cats with sporotrichosis. Interestingly, our study revealed that anti-peptide sera did not react with the recombinant enolase from Felis catus (cats, rFcEno), thus, may not trigger autoimmune response in these felines if used as a vaccine antigen. The immunization with peptide mixture (PeptMix) formulated with Freund adjuvant (FA), induced high levels of antigen-specific IgG, IgG1 and IgG2b antibodies that conferred protection upon passive transference in infected BALB/c mice with S. brasiliensis. We also observed, that the FA+PeptMix formulation induced a Th1/Th2/Th17 cytokine profile ex vivo, associated with protecting effect against the experimental sporotrichosis. Our results suggest that the six SsEno-derived peptides here evaluated, could be used as safe antigens for the development of vaccine strategies against feline sporotrichosis, whether prophylactic or therapeutic.
other
2026-04-27 | CTLA-4 Antisense Oligonucleotide Contributes to Enhanced Immunogenicity of an Adjuvanted Recombinant Sporothrix spp. Enolase Antigen.
Background/Objectives: Sporotrichosis is an emerging zoonotic subcutaneous fungal infection with limited therapeutic options, highlighting the need for improved immunomodulatory strategies. CTLA-4 is an inhibitory immune checkpoint that negatively regulates T-cell activation. In this study, we evaluated whether a CTLA-4 antisense oligonucleotide (CTLA-4 ASO) is associated with enhanced immune responses to an adjuvanted recombinant Sporothrix sp. enolase antigen (rSsEno) formulation. Methods: CTLA-4 ASO uptake, cytotoxicity, and gene-silencing activity were assessed in murine splenocytes in vitro. BALB/c mice were immunized with rSsEno formulated with Montanide Gel 01, either alone or in combination with 5 µg CTLA-4 ASO. Antigen-specific serum antibody responses were quantified by ELISA. Splenocytes from immunized mice were restimulated with enolase, and cytokine production (IFN-γ, IL-2, IL-17, and TNF-α) was measured using Cytometric Bead Array (CBA). Results: CTLA-4 ASO was efficiently internalized by splenocytes and was associated with reduced expression of CTLA-4 without detectable cytotoxicity in vitro. Mice receiving the ASO-supplemented formulation developed significantly higher anti-enolase antibody titers compared to those immunized with adjuvant alone. Upon antigen restimulation, splenocytes from ASO-treated mice produced higher levels of IFN-γ, IL-2, TNF-α, and IL-17, consistent with an enhanced recall response characterized by a mixed Th1/Th17 cytokine profile. Conclusions: CTLA-4 ASO was associated with an enhanced recall response characterized by a mixed Th1/Th17 cytokine profile. These findings suggest a potential immunomodulatory effect of CTLA-4 targeting. Further studies incorporating dose optimization, infection challenge models, and appropriate sequence controls are required to determine the specificity and relevance of these effects for protective immunity against sporotrichosis.
2025-12-08 | Pap1 is an adhesin involved in the interaction of Sporothrix schenckii and Sporothrix brasiliensis with the host.
Sporothrix schenckii and Sporothrix brasiliensis are causative agents of sporotrichosis, a mycosis that affects humans and other mammals. Adhesins are considered among the primary virulence factors of these species; however, their molecular identities are currently scarce. Here, we generated silenced mutant strains in PAP1, encoding a peptidorhamnomannan-associated protein, in both fungal species and compared their phenotypical characterization. PAP1-silenced mutants had normal growth, dimorphism, and morphology, suggesting the gene is not essential. The silenced strains showed defects in adhesion to HeLa cells, laminin, fibronectin, fibrinogen, type-I collagen, and type-II collagen. The S. schenckii silenced mutants showed a significant reduction in the adhesion to elastin, whilst the S. brasiliensis mutant showed impaired ability to bind thrombospondin 1 and to form biofilms. Both sets of PAP1-silenced mutants displayed defects in the cell wall composition, with reduced levels of cell wall rhamnose. The S. schenckii mutants showed a compensatory mechanism increasing cell wall mannose content, while the S. brasiliensis mutants increased cell wall protein levels in compensation to PAP1 silencing. Both mutant sets changed their ability to stimulate cytokine production in human peripheral blood mononuclear cells and monocyte-derived macrophages. In addition, phagocytosis of S. schenckii PAP1-silenced strains was significantly increased, while the S. brasiliensis PAP1-silenced strains were poorly phagocytosed. Finally, PAP1 silencing affected virulence in both species. These results suggest that S. schenckii and S. brasiliensis PAP1 code for a protein with adhesive properties to different ligands. This is a cell wall protein that contributes to Sporothrix virulence and the interaction with immune cells.
2025-10-29 | Dendritic Cell-Based Therapeutic Immunization Induces Th1/Th17 Responses and Reduces Fungal Burden in Experimental Sporotrichosis.
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the latter being more commonly observed in immunosuppressed patients. The limited effectiveness of antifungal treatments against this mycosis, particularly in immunocompromised individuals, has led to the search for more effective and safer therapies. Based on several studies demonstrating the efficient use of dendritic cells as tools for the development of antifungal vaccines, this work aimed to evaluate the protective capacity of bone marrow-derived dendritic cells (BMDCs) activated with cell wall proteins of S. schenckii (SsCWP) in mice infected with S. schenckii sensu stricto. BMDCs were stimulated with SsCWP and analyzed for the surface expression of costimulatory molecules as well as proinflammatory cytokine secretion. Subsequently, mice were vaccinated once or twice to assess immunogenicity, and finally, the therapeutic effect of BMDCs on S. schenckii infection was evaluated. Our results show that SsCWP was able to activate BMDCs. Immunization of healthy mice with SsCWP-stimulated BMDCs induced a balanced Th1/Th17-based immune response. Vaccination of mice previously infected with S. schenckii induced a mixed Th1/Th17 response and reduced fungal burden in the spleen. Overall, these findings demonstrate that therapeutic vaccination with SsCWP-stimulated BMDCs improves fungal control, supporting the notion that dendritic cells represent a promising therapeutic strategy against sporotrichosis.
2025-09-09 | Dendritic Cell–Based Therapeutic Immunization Induces Th1/Th17 Responses and Reduces Fungal Burden in Experimental Sporotrichosis
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the latter being more commonly observed in immunosuppressed patients. The limited effectiveness of antifungal treatments against this mycosis, particularly in immunocompromised individuals, has led to the search for more effective and safer therapies. Based on several studies demonstrating the efficient use of dendritic cells as tools for the development of antifungal vaccines, this work aimed to evaluate the protective capacity of bone marrow–derived dendritic cells (BMDCs) activated with cell wall proteins of S. schenckii (ScCWP) in mice infected with S. schenckii sensu stricto. BMDCs were stimulated with ScCWP and analyzed for the surface expression of costimulatory molecules as well as proinflammatory cytokine secretion. Subsequently, mice were vaccinated once or twice to assess immunogenicity, and finally, the therapeutic effect of BMDCs on S. schenckii infection was evaluated. Our results show that ScCWP were able to activate BMDCs. Immunization of healthy mice with ScCWP-stimulated BMDCs induced a Th17-biased immune response. Vaccination of mice previously infected with S. schenckii induced a mixed Th1/Th17 response and reduced fungal burden in the spleen. Overall, these findings demonstrate that therapeutic vaccination with SsCWP-stimulated BMDCs improves fungal control, supporting the notion that dendritic cells represent a promising therapeutic strategy against sporotrichosis.
2024-04-23 | Silencing of Sporothrix schenckii GP70 Reveals Its Contribution to Fungal Adhesion, Virulence, and the Host–Fungus Interaction
Sporothrix schenckii is one of the etiological agents of sporotrichosis, a cutaneous and subcutaneous infection distributed worldwide. Like other medically relevant fungi, its cell wall is a molecular scaffold to display virulence factors, such as protective pigments, hydrolytic enzymes, and adhesins. Cell wall proteins with adhesive properties have been previously reported, but only a handful of them have been identified and characterized. One of them is Gp70, an abundant cell wall protein mainly found on the surface of yeast-like cells. Since the protein also has a role in the activity of 3-carboxy-cis,cis-muconate cyclase and its abundance is low in highly virulent strains, its role in the Sporothrix–host interaction remains unclear. Here, a set of GP70-silenced strains was generated, and the molecular and phenotypical characterization was performed. The results showed that mutants with high silencing levels showed a significant reduction in the adhesion to laminin and fibrinogen, enzyme activity, and defects in the cell wall composition, which included reduced mannose, rhamnose, and protein content, accompanied by an increment in β-1,3-glucans levels. The cell wall N-linked glycan content was significantly reduced. These strains induced poor TNFα and IL-6 levels when interacting with human peripheral blood mononuclear cells in a dectin-1-, TLR2-, and TLR4-dependent stimulation. The IL-1β and IL-10 levels were significantly higher and were stimulated via dectin-1. Phagocytosis and stimulation of neutrophil extracellular traps by human granulocytes were increased in highly GP70-silenced strains. Furthermore, these mutants showed virulence attenuation in the invertebrate model Galleria mellonella. Our results demonstrate that Gp70 is a versatile protein with adhesin properties, is responsible for the activity of 3-carboxy-cis,cis-muconate cyclase, and is relevant for the S. schenckii–host interaction.
small molecules
2026-09-22 | Molecular and Epidemiological Surveillance of Sporothrix spp. in Cats and Dogs from Southern Brazil.
Sporotrichosis, a subcutaneous mycosis caused by Sporothrix spp., has emerged as a major zoonotic disease in Brazil, primarily driven by Sporothrix brasiliensis. The southern state of Rio Grande do Sul exhibits distinctive ecological and climatic conditions that may shape the persistence and distribution of this pathogen in this region. This study conducted molecular and epidemiological surveillance of feline and canine sporotrichosis in southern Rio Grande do Sul, Brazil. A total of 100 isolates from the culture collection of the Veterinary Mycology Laboratory at the Federal University of Pelotas (UFPel) were analyzed by PCR targeting the calmodulin (CAL) gene for species identification. Fourteen representative isolates were sequenced and subjected to phylogenetic analysis using the Maximum Likelihood method, including reference sequences from Brazil, Paraguay, and Argentina. Epidemiological and clinical variables, including host species, sex, lesion site, and morphology, were evaluated to characterize the epidemiological and clinical profiles of sporotrichosis in the study region. S. brasiliensis and S. schenckii were identified in 97% and 3% of the isolates, respectively. The CAL-based phylogeny confirmed the monophyly of S. brasiliensis and revealed low intraspecific variability with regional clustering among southern Brazilian isolates. When interpreted within the Southern Cone context, the topology indicated a close genetic affinity between isolates from Rio Grande do Sul and reference sequences from Argentina and Paraguay. These findings confirm the territorial expansion of S. brasiliensis across southern Brazil and emphasize the importance of molecular surveillance for detecting and tracking the circulating lineages. Continuous regional monitoring is crucial for strengthening One Health strategies and mitigating the zoonotic spread of sporotrichosis in the Southern Cone.
2026-09-17 | Human sporotrichosis in the Amazon: an emerging zoonosis and its clinical-epidemiological challenges.
The number of sporotrichosis cases in Brazil has been continuously increasing, primarily due to zoonotic transmission in urban areas. This study aimed to analyze the occurrence of human sporotrichosis in a reference center in the Amazon region. This case series study analyzed the medical records of patients diagnosed with sporotrichosis at a dermatology reference service in Northern Brazil. Most patients presented with the localized cutaneous form. Diagnosis was confirmed using clinical and epidemiological criteria, histopathology, and/or culture. Diagnostic suspicion, especially in endemic areas, and early treatment are essential to reduce morbidity, sequelae, and adverse outcomes.
2026-08-19 | Towards standardized antifungal susceptibility testing for Sporothrix brasiliensis.
Sporotrichosis caused by Sporothrix brasiliensis is increasingly reported in South America. Infections in humans are mostly due to zoonotic transmission by cats. For both hosts, itraconazole is the drug of choice despite long treatment duration. Resistance surveillance is warranted, but protocols for antifungal susceptibility testing (AFST) are not always harmonized between laboratories largely due to Sporothrix species being thermally dimorphic and the absence of well-defined consensus methodologies to address how to deal with yeast/mould phases. To standardize susceptibility testing methodology, we propose to modify the current Clinical Laboratory and Standards Institute (CLSI) M38 broth microdilution methodology with S. brasiliensis culture for 7 days at 30°C (rather than 35°C) on potato dextrose agar (PDA), followed by microscopic confirmation of pure mycelial phase. Incubation temperature would also be modified to 30°C for 72 hours. By following this standardized method for at least itraconazole, terbinafine and amphotericin B, S. brasiliensis non-wild-type isolates and correlations with clinical outcomes can be properly investigated. The proposed method is a consensus-oriented interim approach rather than a fully validated standard.
2026-08-18 | Antimicrobial resistance in Staphylococcus spp. isolated from sporotrichosis-affected cats in Brazil: Detection of MRSP and MRSA.
Recently, Brazil has experienced a zoonotic emergence of sporotrichosis. The associated cutaneous lesions are often extensive and slow to heal, thereby providing a gateway for opportunistic bacteria belonging to the normal skin microbiota. Among these, Staphylococcus spp. are of particular concern due to their high prevalence and notable levels of antimicrobial resistance. The objective of this study was to identify and characterize Staphylococcus spp. isolated from the cutaneous wounds of domestic cats undergoing treatment for sporotrichosis and exhibiting clinical signs of secondary bacterial infection. A total of 233 samples from 203 cats were analyzed. Staphylococcus spp. was isolated from 156 samples (67%), with S. aureus (42.3%) and S. felis (25.6%) being the most prevalent. Antimicrobial susceptibility testing revealed high levels of resistance to penicillin (51.9%), erythromycin (28.8%), and clindamycin (19.2%). In contrast, most isolates were susceptible to chloramphenicol (98%), ciprofloxacin (96.7%), and nitrofurantoin (93%). Multidrug-resistant strains were identified in 24% (38/156) of the isolates. Overall, 12 isolates (7.7%) were classified as methicillin-resistant staphylococci, including four methicillin-resistant S. pseudintermedius (MRSP) and one methicillin-resistant S. aureus (MRSA). To investigate the genetic profiles and epidemiological relationships of these isolates, all the MRSP and MRSA strains were subjected to whole-genome sequencing. Among the MRSP isolates, four sequence types (STs) were identified, including ST551, the founder of clonal complex (CC)551, which is commonly associated with infection in dogs. The MRSA isolate belonged to ST1176, a member of CC5, which is a globally prevalent lineage and is frequently associated with nosocomial infections in humans. This study demonstrates that Staphylococcus species, including methicillin-resistant isolates, are frequently present in the wounds of sporotrichosis-infected cats exhibiting clinical signs of secondary bacterial infection. The detection of MRSA and MRSP in a cat highlights an additional public health concern associated with feline sporotrichosis and further reinforces the growing concern regarding antimicrobial resistance in companion animals.
2026-08-12 | Sporotrichosis-induced oxidative imbalance in liver and kidneys of rats infected with Sporothrix brasiliensis: renoprotective effects of farnesol.
Sporothrix brasiliensis is the most virulent species of the genus Sporothrix. Oxidative stress is a key defense mechanism to eliminate this pathogen through generation of reactive oxygen species (ROS). However, S. brasiliensis has developed mechanisms to counteract this response, contributing to its persistence in the host. This paradoxically leads to excessive ROS production in host tissues, inducing oxidative stress. Bearing this in mind, the use of plant-based natural products such as farnesol (terpene) is considered an approach to attenuate oxidative stress, as this compound is known to possess radical scavenging properties. The aim of this study was to determine whether oral administration of farnesol (100 mg/kg) might prevent or attenuate S. brasiliensis-induced in rat renal and hepatic oxidative stress. Renal ROS, thiobarbituric acid reactive substance (TBARS) levels, and both hepatic and renal glutathione S-transferase (GST) activity were significantly higher in infected (group C) compared to uninfected animals (group A), while catalase (CAT) activity was significantly lower. No significant differences were observed between groups regarding hepatic ROS and TBARS levels, as well as superoxide dismutase activity. Farnesol administered to infected animals (group D) attenuated the rise in renal ROS and TBARS levels, as well as GST activity compared to group C. In conclusion, data demonstrated that S. brasiliensis infection induced renal oxidative stress mediated by elevation in ROS levels, initiating membrane lipid damage and diminished CAT activity. The protective effects of farnesol may be attributed to a synergistic effect of its ROS-scavenging ability, diminished lipid damage, and enhanced GST activity.
proteins
2026-06-22 | Antifungal and Therapeutic Evaluation of l- and d‑Enantiomers of a Plant Defensin-Inspired Peptide against Sporothrix schenckii and Sporothrix brasiliensis.
Sporotrichosis is an emerging subcutaneous mycosis and an important public and veterinary health concern in Brazil. The ongoing expansion of feline-associated transmission, particularly involving Sporothrix brasiliensis, has reinforced the need for new antifungal strategies. In this study, we evaluated the antifungal potential of the bioinspired peptide L-CaDef2.1G27‑K44 (L-CDF-GK) and its enantiomer D-CaDef2.1G27‑K44 (D-CDF-GK), derived from a defensin identified in Capsicum annuum fruits. Antifungal activity was assessed through in vitro and in vivo assays, together with the investigation of possible mechanisms of action. The analyses included fungal growth inhibition, cytoplasmic membrane permeabilization, oxidative stress induction, mitochondrial depolarization, and erythrocyte cytotoxicity. In vivo, Galleria mellonella larvae were used to evaluate therapeutic potential by survival analysis, melanization quantification, and hemocyte density determination. Both peptides exhibited significant dose-dependent antifungal activity against Sporothrix schenckii and S. brasiliensis. The L-isoform completely inhibited the growth of both species at 100 μM, whereas the D-isoform inhibited 90% of S. schenckii growth and 70% of S. brasiliensis growth. IC50 analysis and functional assays performed with S. schenckii showed that both peptides induced membrane permeabilization, increased reactive oxygen species production, and loss of mitochondrial membrane potential. In the G. mellonella infection model, lethal dose determination indicated greater virulence of S. brasiliensis. Both peptides showed low toxicity and significantly improved the survival of larvae infected with S. schenckii, with minimal activation of cellular and humoral immune responses. Together, these findings support the potential of CDF-GK-derived peptides as promising candidates for the development of new antifungal strategies against sporotrichosis.
2026-01-01 | Sporothrix schenckii Peptidorhamnomannan-Associated Protein 2 (Pap2) Is Involved in Adhesion and Virulence.
The Sporothrix schenckii cell wall has been widely studied to understand its role in pathogenesis and the infection process. Previously, a component of the cell wall, the peptidorhamnomannan (PRM), was analyzed, and some proteins with unknown function were identified. Among them, the protein encoded by the SPSK_06559 gene stood out for its high abundance within PRM. In this work, in silico analyses were performed to predict the adhesive properties of the SPSK_06559 protein (renamed as Pap2) to extracellular matrix (ECM) components, such as fibrinogen, fibronectin, and type-I and type-II collagen. Subsequently, a recombinant Pap2 (rPap2) version was generated to obtain experimental evidence of its adhesive properties to ECM components. Finally, the role of Pap2 in pathogenesis was assessed in Galleria mellonella larvae. Bioinformatic analyses consistently suggested that Pap2 possesses adhesive properties. Prediction was experimental validated: rPap2 showed strong adhesion to ECM components. Immunization with rPap2 conferred significant protection to G. mellonella larvae against a lethal dose of S. schenckii. Furthermore, preincubation of fungal cells with anti-rPap2 antibodies drastically reduced their ability to kill the larvae. These findings demonstrate that the SPSK_06559 protein (Pap2) participates in the initial adhesion to host tissues. Induction of a protective response through immune priming with rPap2 suggest that Pap2 is a promising immunogenic antigen. Reduction of lethality upon blocking Pap2 confirms its essential role in pathogenesis, positioning it as a potential target for the development of new therapies and vaccines against sporotrichosis.
2025-12-04 | The Cbp1 protein is a peptidorhamnomannan adhesin that contributes to the Sporothrix schenckii virulence.
Sporothrix schenckii pathogenesis has been extensively studied to date, but several proteins of unknown function remain to be assigned to the infectious process. Previously, proteomic data showed that one protein was highly abundant (SPSK_02764) in cell wall peptidorhamnomannan, but no obvious homologs or sequence features hinted at the activity or function of this protein. In this work, in vitro analysis showed that this protein is highly glycosylated and is an adhesin with specificity for type-I and type-II collagen, renaming this protein as Collagen Binding Protein 1 or Cbp1. Yeast-like cells preincubated with anti-SPSK_02764 antibody reduced the ability to kill Galleria mellonella larvae and to induce immune effectors, suggesting a role for this protein in S. schenckii pathogenesis. Bioinformatic analysis suggested that the protein may be a moonlighting protein that is broadly present in Ascomycota and is sequence and structurally conserved. The findings shown here suggest that Cbp1 is another component of the S. schenckii cell wall and participates in host collagen binding, adding a new component to the pathogenesis toolbox of this organism.
2025-11-22 | Immune genes CD247 STAT1 and LCK mediate host-pathogen interactions in sporotrichosis.
Sporotrichosis is a chronic subcutaneous infection caused by the Sporothrix complex, a dimorphic fungus that exhibits significant clinical heterogeneity. However, the molecular targets and underlying mechanisms of Sporothrix globosa infection remain unclear. Therefore, in this study, we aimed to integrate whole-transcriptome sequencing analysis of skin lesion tissues from patients with sporotrichosis and healthy controls. In addition, differential gene expression screening, protein-protein interaction network construction, and functional enrichment analysis. We systematically identified the key immune-related genes, Cluster of Differentiation 247 (CD247), Signal Transducer and Activator of Transcription 1 (STAT1), and Lymphocyte-Specific Tyrosine Kinase (LCK), which are majorly upregulated during infections. The high expression of these genes in the disease group was consistently validated by western blot, quantitative polymerase chain reaction, and immunohistochemistry. Mechanistic analysis revealed the contribution of these genes to sporotrichosis-dysregulated immune response. This occurs by causing excessive activation of the interferon signaling pathway, lymphocyte overactivation, and the JAK-STAT signaling pathway, which leads to the host immune imbalance. This suggests their central role in immune evasion and overactivation during sporotrichosis. In this novel study, we revealed the pathological regulatory role of the CD247-STAT1-LCK molecular network in sporotrichosis, which provided novel insights into fungal-host interactions and identified potential therapeutic targets for immune-modulating antifungal treatments.
2025-11-14 | An anti-adhesive peptide found in extracellular vesicles from Sporothrix brasiliensis and Sporothrix schenckii.
Sporothrix brasiliensis and Sporothrix schenckii are major causative agents of sporotrichosis, a neglected fungal disease with growing public health relevance. These pathogens release extracellular vesicles (EVs) that contribute to host-pathogen interactions, yet their small molecule content remains unexplored. Here, we isolated EVs from both species following growth on solid medium and characterized them using nanoparticle tracking analysis, transmission electron microscopy, proteomics, and untargeted metabolomics. While EVs from each species contained distinct sets of proteins, a subset of conserved components and metabolites was identified, including the dipeptidyl peptidase IV (DPP4) inhibitor isoleucine-proline-isoleucine (IPI), previously described as a protective EV component in Cryptococcus. Functional assays demonstrated that both IPI and an anti-DPP4 antibody significantly impaired fungal adhesion to type I collagen. These findings reveal new layers of molecular complexity in the EVs of Sporothrix spp., highlight the presence of functionally conserved small molecules, and suggest a role for EV-derived peptides in modulating fungal surface interactions with host structures.
antibodies
2025-02-07 | Management of sporotrichosis in patients with inflammatory bowel disease using biological therapy (antitumor necrosis factor).
Antitumor necrosis factor (TNF)-alpha (TNFa) drugs are crucial for treating inflammatory bowel disease (IBD) but may increase opportunistic infection risk. Among such infections, sporotrichosis is a chronic granulomatous disease caused by saprophytic dimorphic fungi of the genus Sporothrix, which occurs worldwide. To date, there have been no reports of sporotrichosis in immunosuppressed IBD patients. The main objectives are to discuss clinical, diagnostic, and therapeutic aspects of sporotrichosis in IBD patients on anti-TNF therapy. We describe three patients with IBD on TNFa therapy who contracted cutaneous-disseminated and extracutaneous sporotrichosis and discuss strategies for managing sporotrichosis and IBD therapy in this scenario. The first case is a patient with ulcerative colitis with mild lymphocutaneous sporotrichosis who did not require discontinuation of anti-TNF agents and methotrexate. The other two patients had rapidly progressive extensive lymphocutaneous disease and disseminated sporotrichosis. These patients required hospitalization, a temporary discontinuation of their biological therapy, and a subsequent switch to vedolizumab. In all cases, the sporotrichosis was successfully treated and none of them experienced serious complications. Sporotrichosis should be considered in anti-TNF IBD patients with opportunistic infections. Early diagnosis, infection treatment, education of cat owners, and population control programs are necessary.
2023-03-30 | Inflammation and epigenetics of sporotrichosis disease.
Sporotrichosis, a fungal disease, is caused by exposure to soil that harbors Sporothrix schenckii or through inhalation of fungal spores. Skin is the most frequently exposed organ making sporotrichosis a primarily dermal disease. Many described reports in the literature suggest a connection of sporotrichosis with cutaneous squamous cell carcinoma with some connection between initial sporotrichosis diagnosis and treatment followed by development of cutaneous squamous cell carcinoma at the very site. Conversely, there is also evidence for sporotrichosis subsequent to skin cancer diagnosis, even after cancer chemotherapy, which points towards weakening of immune response by cancer chemotherapy leading to attack and infection by Sporothrix schenckii. We also propose and focus on inflammation as the connection between sporotrichosis, cancer and even the metastatic spread of cancer. Inflammation-associated IL-6, IFN-γ, natural killer cells and M2-macrophages possibly mechanistically link sporotrichosis with cancer, particularly cutaneous squamous cell carcinoma. These inflammation related factors/cells are regulated epigenetically raising the possibility of epigenetic regulation of sporotrichosis, which has not been described yet in the available literature. Clinical management of inflammation may thus be effective strategy not just against sporotrichosis but also the related onset of cutaneous squamous cell carcinoma and possibly its metastasis to lymph nodes.
2022-08-01 | Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. Schenckii
Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) from S. brasiliensis has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host's immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. We demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.
2022-01-11 | Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. schenckii
Abstract Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix , with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) of Sporothrix spp . is a pathogen associated molecular pattern (PAMP). Interestingly, S. brasiliensis PRM has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host’s immune response and may explain the severity of sporotrichosis caused by S. brasiliensis . Here we demonstrate that S. brasiliensis yeasts and its PRM ( S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis . The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.
2021-11-04 | Transient Foxp3(+) regulatory T-cell depletion enhances protective Th1/Th17 immune response in murine sporotrichosis caused by Sporothrix schenckii.
The role of regulatory T cells (Tregs) on protective immunity in fungal infections, is controversial. Sporotrichosis is an emerging and worldwide-distributed subcutaneous mycosis caused by various related thermodimorphic fungi of the genus Sporothrix. Previously, we showed an elevated percent of Tregs around 21 days post-infection (dpi) in C57BL/6 mice infected with either Sporothrix schenckii or Sporothrix brasiliensis, but the effect of these cells in the ongoing infection was not evaluated. Here, we aim to characterize the role of Foxp3+ Tregs in a subcutaneous S. schenckii infection model. The flow cytometric analyses showed that S. schenckii infection elicited an expansion of a splenic CD4+Foxp3+ population, including a subset of Helioslow+ after ex vivo stimulation with S. schenckii-heat killed yeast. Depletion of Tregs in DEREG mice revealed a reduction of fungal burden in the skin and systemically in liver and kidneys, associated with enhanced Th1 and Th17 responses. Altogether, our results reveal for the first time that Tregs depletion in ongoing S. schenckii infection improves the protective antifungal immunity and these data suggest that Tregs modulation could be explored as a potential therapeutic strategy in sporotrichosis.
vaccines
2026-09-24 | SgtrCypB Formulated with Freund's Adjuvant Confers Protective Immunity Against S. globosa and Partial Cross-Protection Against S. schenckii Infections in Mice.
Sporothrix globosa is the predominant cause of sporotrichosis in China, highlighting the need for effective vaccine strategies. Cyclophilins from pathogenic microorganisms have emerged as potential vaccine antigens. We previously generated a high-yield, high-purity recombinant truncated S. globosa cyclophilin B protein (SgtrCypB) retaining its functional domain. Here, BALB/c mice were immunized subcutaneously with SgtrCypB alone or formulated with Freund's adjuvant to evaluate immunogenicity. Only the adjuvant-formulated vaccine induced a high antibody titer (1:51,200). Then, the infection-challenge experiments compared the SgtrCypB formulated with Freund's adjuvant and PBS formulated with Freund's adjuvant groups. Following challenge, SgtrCypB plus adjuvant reduced cutaneous lesion size (0.6 vs. 1.0 cm at week 1) without significantly affecting ulcer incidence. In systemic S. globosa infection, vaccination increased survival to 90% versus 40% in controls and reduced organ fungal burdens. Partial cross-protection was observed against S. schenckii, with 60% versus 20% survival and lower fungal burdens in the kidneys and lungs. Protection against C. albicans was minimal. These findings identify SgtrCypB as a promising protective antigen against S. globosa and S. schenckii and support further evaluation with clinically applicable adjuvants.
2025-12-22 | Sporothrix brasiliensis and cats: understanding the disease and the promising potential of veterinary antifungal vaccination for a healthier future of both humans and animals
Abstract Sporotrichosis is a subcutaneous fungal infection caused by species of the Sporothrix genus that affects both humans and animals. Sporothrix brasiliensis is a dimorphic fungus that exists in a mycelial and conidial phase in nature and is a yeast in its parasitic stage or when cultured at 37°C. Since its first identification in animals in 1907, the disease has become a significant concern, especially given the increasing number of cases in cats, particularly in urban areas. This has contributed to an increase in zoonotic transmission and the current epidemic of sporotrichosis in Brazil. Virulent strains of S. brasiliensis , combined with the increased susceptibility of felines, have exacerbated the public health challenge posed by sporotrichosis. As with other infectious diseases, immunomodulation presents a promising strategy for the prevention, treatment, and control of sporotrichosis in animals, potentially reducing zoonotic transmission. This review examines the role of cats in the transmission of this disease, the interactions between Sporothrix species and the host immune system, and the progress in the development of antifungal vaccines. We also highlight ongoing research into vaccine strategies. Ultimately, our goal is to encourage further dialog on effective approaches to control the rapid spread of zoonotic sporotrichosis. Graphical Abstract Sporothrix brasiliensis drives a growing sporotrichosis epidemic in Brazil, with domestic cats serving as the key zoonotic reservoir. This review examines the feline-driven transmission cycle, host‒pathogen immune interactions, and current progress in vaccine development. Immunomodulation through feline vaccination has emerged as a crucial strategy for breaking the transmission chain and controlling this public health threat.
2025-01-27 | Sporothrix brasiliensis Gp70 is a cell wall protein required for adhesion, proper interaction with innate immune cells, and virulence.
Sporothrix brasiliensis is one of the leading etiological agents of sporotrichosis, a cutaneous and subcutaneous mycosis worldwide distributed. This organism has been recently associated with epidemic outbreaks in Brazil. Despite the medical relevance of this species, little is known about its virulence factors, and most of the information on this subject is extrapolated from Sporothrix schenckii. Here, we generated S. brasiliensis mutants, where GP70 was silenced. In S. schenckii, this gene encodes a glycoprotein with adhesive properties required for virulence. The S. brasiliensis GP70 silencing led to an abnormal cellular phenotype, with smaller, round yeast-like cells that aggregate. Cell aggregation was disrupted with glucanase, suggesting this phenotype is linked to changes in the cell wall. The cell wall characterization confirmed changes in the structural polysaccharide β-1,3-glucan, which increased in quantity and exposure at the cell surface. This was accompanied by a reduction in protein content and N-linked glycans. Mutant strains with high GP70-silencing levels showed minimal levels of 3-carboxy-cis,cis-muconate cyclase activity, this glycoprotein's predicted enzyme function, and decreased ability to bind laminin and fibronectin. These phenotypical changes coincided with abnormal interaction with human peripheral blood mononuclear cells, where production of IL-1β, IL-17, and IL-22 was reduced and the strong dependence on cytokine stimulation via mannose receptor was lost. Phagocytosis by monocyte-derived macrophages was increased and virulence attenuated in a Galleria mellonella larvae. In conclusion, Gp70 is an abundant cell wall glycoprotein in S. brasiliensis that contributes to virulence and proper interaction with innate immnune cells.
2022-10-07 | Recombinant phage displaying ToAP2D peptide with antifungal activity against Sporothrix globosa
We designed and synthesized recombinant phage nanofibers displaying ToAP2D peptide and investigated their antifungal effect on Sporothrix and the corresponding mechanism. Antimicrobial peptide, ToAP2D, was used as the template. The effect of synthesized recombinant phages on the immune function of CD4+ T lymphocytes in mice was tested using an enzyme-linked immunosorbent assay. The therapeutic effect and safety of recombinant phage administration on Sporothrix-infected BALB/c mice were evaluated based on survival analysis, histopathological changes, and renal and liver functions. The successfully prepared recombinant phage displaying ToAP2D peptides significantly inhibited Sporothrix growth. According to the scanning electron microscopy results, the recombinant phage caused shrinkage and rupture of Sporothrix globosa, leading to leakage of the contents. The Hoechst/propidium iodide double staining test indicated that the recombinant phage could induce cell apoptosis of Sporothrix globosa. The apoptotic pathway might be due to the accumulation of reactive oxygen species in large quantities in cells, activating caspase dependence; this reduced inflammation, prolonged the survival time, and enhanced levels of IFN-γ and IL-17 in mice. We believe that recombinant phage inhibits Sporothrix growth by adjusting the immune response of mice, inducing Sporothrix apoptosis and improving animal survival. This study offers a new approach to preparing antimicrobial peptides.
2022-05-17 | A Sporothrix spp. enolase derived multi-epitope vaccine confers protective response in BALB/c mice challenged with Sporothrix brasiliensis.
Sporotrichosis is a cosmopolitan mycosis caused by pathogenic species of Sporothrix genus, that in Brazil is often acquired by zoonotic transmission involved infected cats with S. brasiliensis. Previous studies showed that the Sporothrix spp. recombinant enolase (rSsEno), a multifunctional protein with immunogenic properties, could be a promising target for vaccination against sporotrichosis in cats. Nevertheless, the considerable sequence identity (62%) of SsEno with its feline counterpart is a great concern. Here, we report the identification in silico, chemical synthesis and biological validation of six peptides of SsEno with low sequence identity to its cat orthologue. All synthesized peptides exhibit B-cell epitopes on the molecular surface of SsEno and proved to be highly reactive with the serum of infected mice with S. brasiliensis and sera of cats with sporotrichosis. Interestingly, our study revealed that anti-peptide sera did not react with the recombinant enolase from Felis catus (cats, rFcEno), thus, may not trigger autoimmune response in these felines if used as a vaccine antigen. The immunization with peptide mixture (PeptMix) formulated with Freund adjuvant (FA), induced high levels of antigen-specific IgG, IgG1 and IgG2b antibodies that conferred protection upon passive transference in infected BALB/c mice with S. brasiliensis. We also observed, that the FA+PeptMix formulation induced a Th1/Th2/Th17 cytokine profile ex vivo, associated with protecting effect against the experimental sporotrichosis. Our results suggest that the six SsEno-derived peptides here evaluated, could be used as safe antigens for the development of vaccine strategies against feline sporotrichosis, whether prophylactic or therapeutic.
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2026-04-27 | CTLA-4 Antisense Oligonucleotide Contributes to Enhanced Immunogenicity of an Adjuvanted Recombinant Sporothrix spp. Enolase Antigen.
Background/Objectives: Sporotrichosis is an emerging zoonotic subcutaneous fungal infection with limited therapeutic options, highlighting the need for improved immunomodulatory strategies. CTLA-4 is an inhibitory immune checkpoint that negatively regulates T-cell activation. In this study, we evaluated whether a CTLA-4 antisense oligonucleotide (CTLA-4 ASO) is associated with enhanced immune responses to an adjuvanted recombinant Sporothrix sp. enolase antigen (rSsEno) formulation. Methods: CTLA-4 ASO uptake, cytotoxicity, and gene-silencing activity were assessed in murine splenocytes in vitro. BALB/c mice were immunized with rSsEno formulated with Montanide Gel 01, either alone or in combination with 5 µg CTLA-4 ASO. Antigen-specific serum antibody responses were quantified by ELISA. Splenocytes from immunized mice were restimulated with enolase, and cytokine production (IFN-γ, IL-2, IL-17, and TNF-α) was measured using Cytometric Bead Array (CBA). Results: CTLA-4 ASO was efficiently internalized by splenocytes and was associated with reduced expression of CTLA-4 without detectable cytotoxicity in vitro. Mice receiving the ASO-supplemented formulation developed significantly higher anti-enolase antibody titers compared to those immunized with adjuvant alone. Upon antigen restimulation, splenocytes from ASO-treated mice produced higher levels of IFN-γ, IL-2, TNF-α, and IL-17, consistent with an enhanced recall response characterized by a mixed Th1/Th17 cytokine profile. Conclusions: CTLA-4 ASO was associated with an enhanced recall response characterized by a mixed Th1/Th17 cytokine profile. These findings suggest a potential immunomodulatory effect of CTLA-4 targeting. Further studies incorporating dose optimization, infection challenge models, and appropriate sequence controls are required to determine the specificity and relevance of these effects for protective immunity against sporotrichosis.
2025-12-08 | Pap1 is an adhesin involved in the interaction of Sporothrix schenckii and Sporothrix brasiliensis with the host.
Sporothrix schenckii and Sporothrix brasiliensis are causative agents of sporotrichosis, a mycosis that affects humans and other mammals. Adhesins are considered among the primary virulence factors of these species; however, their molecular identities are currently scarce. Here, we generated silenced mutant strains in PAP1, encoding a peptidorhamnomannan-associated protein, in both fungal species and compared their phenotypical characterization. PAP1-silenced mutants had normal growth, dimorphism, and morphology, suggesting the gene is not essential. The silenced strains showed defects in adhesion to HeLa cells, laminin, fibronectin, fibrinogen, type-I collagen, and type-II collagen. The S. schenckii silenced mutants showed a significant reduction in the adhesion to elastin, whilst the S. brasiliensis mutant showed impaired ability to bind thrombospondin 1 and to form biofilms. Both sets of PAP1-silenced mutants displayed defects in the cell wall composition, with reduced levels of cell wall rhamnose. The S. schenckii mutants showed a compensatory mechanism increasing cell wall mannose content, while the S. brasiliensis mutants increased cell wall protein levels in compensation to PAP1 silencing. Both mutant sets changed their ability to stimulate cytokine production in human peripheral blood mononuclear cells and monocyte-derived macrophages. In addition, phagocytosis of S. schenckii PAP1-silenced strains was significantly increased, while the S. brasiliensis PAP1-silenced strains were poorly phagocytosed. Finally, PAP1 silencing affected virulence in both species. These results suggest that S. schenckii and S. brasiliensis PAP1 code for a protein with adhesive properties to different ligands. This is a cell wall protein that contributes to Sporothrix virulence and the interaction with immune cells.
2025-10-29 | Dendritic Cell-Based Therapeutic Immunization Induces Th1/Th17 Responses and Reduces Fungal Burden in Experimental Sporotrichosis.
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the latter being more commonly observed in immunosuppressed patients. The limited effectiveness of antifungal treatments against this mycosis, particularly in immunocompromised individuals, has led to the search for more effective and safer therapies. Based on several studies demonstrating the efficient use of dendritic cells as tools for the development of antifungal vaccines, this work aimed to evaluate the protective capacity of bone marrow-derived dendritic cells (BMDCs) activated with cell wall proteins of S. schenckii (SsCWP) in mice infected with S. schenckii sensu stricto. BMDCs were stimulated with SsCWP and analyzed for the surface expression of costimulatory molecules as well as proinflammatory cytokine secretion. Subsequently, mice were vaccinated once or twice to assess immunogenicity, and finally, the therapeutic effect of BMDCs on S. schenckii infection was evaluated. Our results show that SsCWP was able to activate BMDCs. Immunization of healthy mice with SsCWP-stimulated BMDCs induced a balanced Th1/Th17-based immune response. Vaccination of mice previously infected with S. schenckii induced a mixed Th1/Th17 response and reduced fungal burden in the spleen. Overall, these findings demonstrate that therapeutic vaccination with SsCWP-stimulated BMDCs improves fungal control, supporting the notion that dendritic cells represent a promising therapeutic strategy against sporotrichosis.
2025-09-09 | Dendritic Cell–Based Therapeutic Immunization Induces Th1/Th17 Responses and Reduces Fungal Burden in Experimental Sporotrichosis
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the latter being more commonly observed in immunosuppressed patients. The limited effectiveness of antifungal treatments against this mycosis, particularly in immunocompromised individuals, has led to the search for more effective and safer therapies. Based on several studies demonstrating the efficient use of dendritic cells as tools for the development of antifungal vaccines, this work aimed to evaluate the protective capacity of bone marrow–derived dendritic cells (BMDCs) activated with cell wall proteins of S. schenckii (ScCWP) in mice infected with S. schenckii sensu stricto. BMDCs were stimulated with ScCWP and analyzed for the surface expression of costimulatory molecules as well as proinflammatory cytokine secretion. Subsequently, mice were vaccinated once or twice to assess immunogenicity, and finally, the therapeutic effect of BMDCs on S. schenckii infection was evaluated. Our results show that ScCWP were able to activate BMDCs. Immunization of healthy mice with ScCWP-stimulated BMDCs induced a Th17-biased immune response. Vaccination of mice previously infected with S. schenckii induced a mixed Th1/Th17 response and reduced fungal burden in the spleen. Overall, these findings demonstrate that therapeutic vaccination with SsCWP-stimulated BMDCs improves fungal control, supporting the notion that dendritic cells represent a promising therapeutic strategy against sporotrichosis.
2024-04-23 | Silencing of Sporothrix schenckii GP70 Reveals Its Contribution to Fungal Adhesion, Virulence, and the Host–Fungus Interaction
Sporothrix schenckii is one of the etiological agents of sporotrichosis, a cutaneous and subcutaneous infection distributed worldwide. Like other medically relevant fungi, its cell wall is a molecular scaffold to display virulence factors, such as protective pigments, hydrolytic enzymes, and adhesins. Cell wall proteins with adhesive properties have been previously reported, but only a handful of them have been identified and characterized. One of them is Gp70, an abundant cell wall protein mainly found on the surface of yeast-like cells. Since the protein also has a role in the activity of 3-carboxy-cis,cis-muconate cyclase and its abundance is low in highly virulent strains, its role in the Sporothrix–host interaction remains unclear. Here, a set of GP70-silenced strains was generated, and the molecular and phenotypical characterization was performed. The results showed that mutants with high silencing levels showed a significant reduction in the adhesion to laminin and fibrinogen, enzyme activity, and defects in the cell wall composition, which included reduced mannose, rhamnose, and protein content, accompanied by an increment in β-1,3-glucans levels. The cell wall N-linked glycan content was significantly reduced. These strains induced poor TNFα and IL-6 levels when interacting with human peripheral blood mononuclear cells in a dectin-1-, TLR2-, and TLR4-dependent stimulation. The IL-1β and IL-10 levels were significantly higher and were stimulated via dectin-1. Phagocytosis and stimulation of neutrophil extracellular traps by human granulocytes were increased in highly GP70-silenced strains. Furthermore, these mutants showed virulence attenuation in the invertebrate model Galleria mellonella. Our results demonstrate that Gp70 is a versatile protein with adhesin properties, is responsible for the activity of 3-carboxy-cis,cis-muconate cyclase, and is relevant for the S. schenckii–host interaction.
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Drug Discovery Landscape
1 orphan drug designation for Sporotrichosis.
1 orphan drug designation for Sporotrichosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Amphotericin B lipid complex | small molecules | FDA | — | The Liposome Company, Inc. |
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