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A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 16955

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Dr. Sonia Rozental

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Programa de Biologia Celular e Parasitologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Interests: fungal biology; mycoses; host-fungal interaction; antifungal treatment and resistance

Dr. Luana Pereira Borba-Santos

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Programa de Biologia Celular e Parasitologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Interests: medical mycology; fungal biology; antifungal development; drug repurposing

Special Issue Information

Dear Colleagues,

The pathogenic and thermodimorphic species of the Sporothrix genus (Sporothrix brasiliensis, Sporothrix globosa, and Sporothrix schenckii) are the main causative agents of sporotrichosis. Sporotrichosis is the most common human subcutaneous mycosis worldwide and can also affect animals (especially cats). This disease can be acquired as sapronosis or zoonosis, and zoonotic sporotrichosis is currently endemic in Brazil and expanding to other Latin American countries.

The Special Issue “Sporothrix Emerging Investigators” intends to present relevant aspects of Sporothrix pathogenic species and sporotrichosis, including the epidemiology, diagnosis, treatment, host–Sporothrix interaction, fungal cell biology, the activity of novel compounds, and resistance mechanisms. Original articles, case studies, and reviews are all welcome.

Dr. Sonia Rozental
Dr. Luana Pereira Borba-Santos
Guest Editors

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Keywords

sporotrichosis
Sporothrix
fungal biology
host–fungal interactions
antifungal susceptibility
antifungal discovery
fungal diagnostics

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Published Papers (7 papers)

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Research

21 pages, 3395 KiB

Open AccessArticle

Human and Feline Sporotrichosis in a Reference Center of Southeastern Brazil: Genetic Differentiation, Diversity, and Antifungal Susceptibility of Sporothrix Species

by Sarah Santos Gonçalves, Isabela da Cruz Bahiense Rocha, Bruno Carneiro Rediguieri, Jamile Ambrósio de Carvalho, Simone Bravim Maifrede, Wdson Luis Lima Kruschewsky, Aloísio Falqueto and Anderson Messias Rodrigues

J. Fungi 2023, 9(8), 831; https://doi.org/10.3390/jof9080831 - 7 Aug 2023

Cited by 9 | Viewed by 2564

Abstract

Sporotrichosis is a neglected subcutaneous fungal infection that affects humans and animals worldwide caused by species belonging to the genus Sporothrix. This study aims to examine the range of genetic variations, assess molecular epidemiology significance, and explore potential modes of transmission of the Sporothrix species associated with the current sporotrichosis outbreaks in Espírito Santo, Brazil. In this investigation, 262 samples were evaluated, including 142 from humans and 120 from felines, collected between 2016 and 2021. The isolates were identified based on morphological and molecular characteristics. Sexual idiomorphs were determined by mating-type PCR using primers specific to the MAT1-1 and MAT1-2 loci. Amplified fragment length polymorphism (AFLP) was employed to assess the genetic variability of Sporothrix spp. Finally, antifungal susceptibility testing was performed following the CLSI M38-A2 protocol. Of the 142 human samples, 125 were identified as S. brasiliensis and 17 as S. schenckii s. str. The presence of S. brasiliensis was overwhelming (100%) during outbreaks, highlighting the significant role of domestic cats in the emergence of this species. Heterothallism was the only observed mating strategy. However, the MAT1-2 idiomorph was predominant in cases of cat-transmitted sporotrichosis (χ² = 202.976; p < 0.0001). Our AFLP results show significant intraspecific variability observed among S. brasiliensis isolates in Espírito Santo. Different genotypes forming subgroups within the same population suggest that these isolates do not originate from a single ancestor, indicating multiple emergences. Furthermore, terbinafine was the antifungal with the best results in vitro. However, in clinical practice, itraconazole remains the primary treatment choice. Sporotrichosis continues to advance in the state; therefore, the health system must outline one-health strategies to contain the disease to prevent future epidemics. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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21 pages, 6991 KiB

Open AccessArticle

Metabolic Plasticity and Virulence-Associated Factors of Sporothrix brasiliensis Strains Related to Familiar Outbreaks of Cat-to-Human Transmitted Sporotrichosis

by Dario Corrêa-Junior, Iara Bastos de Andrade, Vinicius Alves, Igor Avellar-Moura, Tânia Rodrigues-Alves, Vanessa Brito de Souza Rabello, Glauber R. de S. Araújo, Luana Pereira Borba-Santos, Rosely Maria Zancopé-Oliveira, Rodrigo Almeida-Paes and Susana Frases

J. Fungi 2023, 9(7), 724; https://doi.org/10.3390/jof9070724 - 4 Jul 2023

Cited by 2 | Viewed by 1411

Abstract

Sporothrix brasiliensis is the main agent of zoonotic sporotrichosis transmitted by domestic cats in South America. In humans, sporotrichosis commonly presents with cutaneous or lymphocutaneous lesions, and in cats, with multiple ulcerated skin lesions associated with enlarged lymph nodes and respiratory signs. Fungal virulence factors may affect the clinical presentation of the mycoses. Sporothrix spp. present some virulence factors. This study aims to compare 24 S. brasiliensis strains from 12 familiar outbreaks of cat-to-human transmitted sporotrichosis. Fungal growth in different substrates, thermotolerance, resistance to oxidative stress, and production of enzymes were evaluated. An invertebrate model of experimental infection was used to compare the virulence of the strains. The strains grew well on glucose and N-acetyl-D-glucosamine but poorly on lactate. Their thermotolerance was moderate to high. All strains were susceptible to hydrogen peroxide, and the majority produced hemolysins but not phospholipase and esterase. There was no significant difference in the putative virulence-associated factors studied among the different hosts. Moreover, strains isolated from a human and a cat from four familiar outbreaks presented a very similar profile of expression of these factors, reinforcing the zoonotic transmission of S. brasiliensis in Brazil and demonstrating the plasticity of this species in the production of virulence factors. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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21 pages, 3797 KiB

Open AccessArticle

Differential Recognition of Clinically Relevant Sporothrix Species by Human Mononuclear Cells

by Laura C. García-Carnero, Iván Martínez-Duncker, Manuela Gómez-Gaviria and Héctor M. Mora-Montes

J. Fungi 2023, 9(4), 448; https://doi.org/10.3390/jof9040448 - 6 Apr 2023

Cited by 6 | Viewed by 2286

Abstract

Sporotrichosis is a human and animal fungal infection distributed worldwide that is caused by the thermodimorphic species of the Sporothrix pathogenic clade, which includes Sporothrix brasiliensis, Sporothrix schenckii, and Sporothrix globosa. The cell wall composition and the immune response against the Sporothrix species have been studied mainly in S. brasiliensis and S. schenckii, whilst little is known about the S. globosa cell wall and the immune response that its components trigger. Therefore, in this study, we aimed to analyze the cell wall composition of S. globosa in three morphologies (germlings, conidia, and yeast-like cells) and the differences in cytokine production when human peripheral blood mononuclear cells (PBMCs) interact with these morphotypes, using S. schenckii and S. brasiliensis as a comparison. We found that S. globosa conidia and yeast-like cells have a higher cell wall chitin content, while all three morphologies have a higher β-1,3-glucan content, which was found most exposed at the cell surface when compared to S. schenckii and S. brasiliensis. In addition, S. globosa has lower levels of mannose- and rhamnose-based glycoconjugates, as well as of N- and O-linked glycans, indicating that this fungal cell wall has species-specific proportions and organization of its components. When interacting with PBMCs, S. brasiliensis and S. globosa showed a similar cytokine stimulation profile, but with a higher stimulation of IL-10 by S. globosa. Additionally, when the inner cell wall components of S. globosa were exposed at the surface or N- and O-glycans were removed, the cytokine production profile of this species in its three morphotypes did not significantly change, contrasting with the S. schenckii and S. brasiliensis species that showed different cytokine profiles depending on the treatment applied to the walls. In addition, it was found that the anti-inflammatory response stimulated by S. globosa was dependent on the activation of dectin-1, mannose receptor, and TLR2, but not TLR4. All of these results indicate that the cell wall composition and structure of the three Sporothrix species in the three morphologies are different, affecting their interaction with human PBMCs and generating species-specific cytokine profiles. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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34 pages, 16899 KiB

Open AccessArticle

High-Throughput Microsatellite Markers Development for Genetic Characterization of Emerging Sporothrix Species

by Luiza Chaves de Miranda Leonhardt Losada, Ruan Campos Monteiro, Jamile Ambrósio de Carvalho, Ferry Hagen, Matthew C. Fisher, Bram Spruijtenburg, Jacques F. Meis, Theun de Groot, Sarah Santos Gonçalves, Ricardo Negroni, Rui Kano, Alexandro Bonifaz, Zoilo Pires de Camargo and Anderson Messias Rodrigues

J. Fungi 2023, 9(3), 354; https://doi.org/10.3390/jof9030354 - 14 Mar 2023

Cited by 12 | Viewed by 3202

Abstract

Sporotrichosis is the main subcutaneous mycosis worldwide transmitted by animal or plant vectors and often escalates to outbreaks or epidemics. The current cat-transmitted sporotrichosis driven by Sporothrix brasiliensis has become a significant public health issue in South America. Transmission dynamics remain enigmatic due to the lack of development of polymorphic markers for molecular epidemiological analysis. This study used a high-throughput mining strategy to characterize simple sequence repeat (SSR) markers from Sporothrix genomes. A total of 118,140–143,912 SSR loci were identified (82,841–98,369 unique markers), with a 3651.55–3804.65 SSR/Mb density and a majority of dinucleotides motifs (GC/CG). We developed a panel of 15 highly polymorphic SSR markers suitable for genotyping S. brasiliensis, S. schenckii, and S. globosa. PCR amplification revealed 240 alleles in 180 Sporothrix isolates with excellent polymorphic information content (PIC = 0.9101), expected heterozygosity (H = 0.9159), and discriminating power (D = 0.7127), supporting the effectiveness of SSR markers in uncovering cryptic genetic diversity. A systematic population genetic study estimated three clusters, corresponding to S. brasiliensis (population 1, n = 97), S. schenckii (population 2, n = 49), and S. globosa (population 3, n = 34), with a weak signature of mixed ancestry between populations 1 and 2 or 3 and 2. Partitioning of genetic variation via AMOVA revealed highly structured populations (ΦPT = 0.539; Nm = 0.213; p < 0.0001), with approximately equivalent genetic variability within (46%) and between (54%) populations. Analysis of SSR diversity supports Rio de Janeiro (RJ) as the center of origin for contemporary S. brasiliensis infections. The recent emergence of cat-transmitted sporotrichosis in northeastern Brazil indicates an RJ-Northeast migration resulting in founder effects during the introduction of diseased animals into sporotrichosis-free areas. Our results demonstrated high cross-species transferability, reproducibility, and informativeness of SSR genetic markers, helping dissect deep and fine-scale genetic structures and guiding decision making to mitigate the harmful effects of the expansion of cat-transmitted sporotrichosis. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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9 pages, 599 KiB

Open AccessArticle

Severe Sporotrichosis Caused by Sporothrix brasiliensis: Antifungal Susceptibility and Clinical Outcomes

by Vivian Fichman, Fernando Almeida-Silva, Dayvison Francis Saraiva Freitas, Rosely Maria Zancopé-Oliveira, Maria Clara Gutierrez-Galhardo and Rodrigo Almeida-Paes

J. Fungi 2023, 9(1), 49; https://doi.org/10.3390/jof9010049 - 28 Dec 2022

Cited by 6 | Viewed by 1743

Abstract

Itraconazole is the first choice for treating sporotrichosis. Amphotericin B is indicated for severe and disseminated forms. The aim of the study was to evaluate the antifungal susceptibility of Sporothrix brasiliensis strains isolated from patients with severe sporotrichosis treated with amphotericin B and correlate with clinical outcomes. Clinical and epidemiological data were obtained from severe sporotrichosis cases caused by S. brasiliensis. Antifungal susceptibility tests against amphotericin B, itraconazole, terbinafine, posaconazole, and 5-flucytosine were performed. Moreover, possible synergisms between amphotericin B and posaconazole or 5-flucytosine were assessed. Relationships between clinical and laboratorial data were then analyzed. Forty-six S. brasiliensis isolates from 37 patients were studied. Clinical forms included disseminated (94.6%) and disseminated cutaneous sporotrichosis (5.4%). The median treatment time was 784 days (range: 7 to 3115 days). Cure occurred in 45.9% of the cases and death due to sporotrichosis in 24.3%. Forty-three (93.5%) S. brasiliensis isolates were classified as wild-type for all the antifungals tested according to their in vitro antifungal susceptibility. There was no synergism for the combinations studied. Finally, we found no association between higher Minimal Inhibitory Concentration (MIC) values of amphotericin B or itraconazole with unfavorable outcomes; however, there were higher MIC values of itraconazole in strains isolated from alcoholic patients. Possibly, clinical factors, such as the extent of dissemination, immunosuppression, and late treatment onset, are the main determinants of patient outcomes, rather than antifungal resistance. The current study suggests that the need to use amphotericin B therapy is not associated with the emergence of S. brasiliensis resistant strains. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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23 pages, 2457 KiB

Open AccessArticle

Silencing of ROT2, the Encoding Gene of the Endoplasmic Reticulum Glucosidase II, Affects the Cell Wall and the Sporothrix schenckii–Host Interaction

by Luz A. López-Ramírez, Iván Martínez-Duncker, Anayeli Márquez-Márquez, Ana P. Vargas-Macías and Héctor M. Mora-Montes

J. Fungi 2022, 8(11), 1220; https://doi.org/10.3390/jof8111220 - 18 Nov 2022

Cited by 3 | Viewed by 1970

Abstract

Sporothrix schenckii is a member of the Sporothrix pathogenic clade and one of the most common etiological agents of sporotrichosis, a subcutaneous fungal infection that affects both animal and human beings. Like other fungal pathogens, the Sporothrix cell wall is composed of structural polysaccharides and glycoproteins that are covalently modified with both N-linked and O-linked glycans. Thus far, little is known about the N-linked glycosylation pathway in this organism or its contribution to cell wall composition and interaction with the host. Here, we silenced ROT2, which encodes the catalytic subunit of the endoplasmic reticulum α-glucosidase II, a processing enzyme key for the N-linked glycan core processing. Silencing of ROT2 led to the accumulation of the Glc₂Man₉GlcNAC₂ glycan core at the cell wall and a reduction in the total content of N-linked glycans found in the wall. However, the highly silenced mutants showed a compensatory mechanism with increased content of cell wall O-linked glycans. The phenotype of mutants with intermediate levels of ROT2 silencing was more informative, as they showed changes in the cell wall composition and exposure of β-1.3-glucans and chitin at the cell surface. Furthermore, the ability to stimulate cytokine production by human mononuclear cells was affected, along with the phagocytosis by human monocyte-derived macrophages, in a mannose receptor-, complement receptor 3-, and TLR4-dependent stimulation. In an insect model of experimental sporotrichosis, these mutant cells showed virulence attenuation. In conclusion, S. schenckii ROT2 is required for proper N-linked glycosylation, cell wall organization and composition, and interaction with the host. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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14 pages, 2497 KiB

Open AccessArticle

Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species

by Luana Pereira Borba-Santos, Rodrigo Rollin-Pinheiro, Yasmin da Silva Fontes, Giulia Maria Pires dos Santos, Glauber Ribeiro de Sousa Araújo, Anderson Messias Rodrigues, Allan J. Guimarães, Wanderley de Souza, Susana Frases, Antonio Ferreira-Pereira, Eliana Barreto-Bergter and Sonia Rozental

J. Fungi 2022, 8(10), 1004; https://doi.org/10.3390/jof8101004 - 25 Sep 2022

Cited by 13 | Viewed by 2982

Abstract

The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching for new drug candidates. In this study, we screened the Pandemic Response Box library (Medicines for Malaria Venture) of 400 diverse molecules against the Sporothrix pathogenic species. The initial screen identified twenty-four candidates that inhibited the growth of Sporothrix brasiliensis by more than 80%. Some of these compounds are known to display antifungal activity, including olorofim (MMV1782354), a new antifungal drug. Olorofim inhibited and killed the yeasts of S. brasiliensis, S. schenckii, and S. globosa at concentrations lower than itraconazole, and it also showed antibiofilm activity. According to the results obtained by fluorimetry, electron microscopy, and particle characterization analyses, we observed that olorofim induced profound alterations on the cell surface and cell cycle arrest in S. brasiliensis yeasts. We also verified that these morphophysiological alterations impaired their ability to adhere to keratinocytes in vitro. Our results indicate that olorofim is a promising new antifungal against sporotrichosis agents. Full article

(This article belongs to the Special Issue Sporothrix Emerging Investigators)

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