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![Scheme of glucosylceramide biosynthetic pathway in Scedosporium boydii according to Rollin-Pinheiro and colleagues [27]](publication/344615183/figure/fig2/AS:962058900213763@1606384124789/Scheme-of-glucosylceramide-biosynthetic-pathway-in-Scedosporium-boydii-according-to.png)
Scheme of glucosylceramide biosynthetic pathway in Scedosporium boydii according to Rollin-Pinheiro and colleagues [27]
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Scedosporium species are filamentous fungi usually found in sewage and soil from human-impacted areas. They cause a wide range of diseases in humans, from superficial infections, such as mycetoma, to invasive and disseminated cases, especially associated in immunocompromised patients. Scedosporium species are also related to lung colonization in in...
Citations
... Although the process or functions could not be determined for all DEGs, several important enzymes dedicated to processes associated with cell-wall metabolism were overexpressed in M1 relative to WT, such as a neutral/alkaline ceramidase. The fungal cell wall is a dynamic and complex structure in which polysaccharides, oligosaccharides, lipids, and proteins are intertwined [24]. For the first time, the transcriptomic analysis of a ∆PIG1 fungal strain was performed. ...
Scedosporium apiospermum is a saprophytic filamentous fungus involved in human infections, of which the virulence factors that contribute to pathogenesis are still poorly characterized. In particular, little is known about the specific role of dihydroxynaphtalene (DHN)-melanin, located on the external layer of the conidia cell wall. We previously identified a transcription factor, PIG1, which may be involved in DHN-melanin biosynthesis. To elucidate the role of PIG1 and DHN-melanin in S. apiospermum, a CRISPR-Cas9-mediated PIG1 deletion was carried out from two parental strains to evaluate its impact on melanin biosynthesis, conidia cell-wall assembly, and resistance to stress, including the ability to survive macrophage engulfment. ΔPIG1 mutants did not produce melanin and showed a disorganized and thinner cell wall, resulting in a lower survival rate when exposed to oxidizing conditions, or high temperature. The absence of melanin increased the exposure of antigenic patterns on the conidia surface. PIG1 regulates the melanization of S. apiospermum conidia, and is involved in the survival to environmental injuries and to the host immune response, that might participate in virulence. Moreover, a transcriptomic analysis was performed to explain the observed aberrant septate conidia morphology and found differentially expressed genes, underlining the pleiotropic function of PIG1.
... Several determinants of pathogenesis have a role in the manifestation of disease [100], associated with germination [108], biofilm formation [109], destruction of lung epithelial cells [109], and infiltration of blood vessels [110], resulting in widespread dissemination to distal organs [110]. Important molecules in the fungal cell wall that enhance fungal virulence include peptidorhamnomannan, glucosylceramide, and melanin [111]. The susceptibility of this fungus to innate immunity, particularly to neutrophils, may explain the high rate of prevalence in neutropenic patients [106]. ...
Background:
Lomentospora prolificans, a rare, highly virulent filamentous fungus with high rates of intrinsic resistance to antifungals, has been associated with different types of infections in immunocompromised as well as immunocompetent individuals.
Objective:
To systematically address all relevant evidence regarding L. prolificans disseminated infections in the literature.
Methods:
We searched Medline via PubMed and Scopus databases through July 2022. We performed a qualitative synthesis of published articles reporting disseminated infections from L. prolificans in humans.
Results:
A total of 87 studies describing 142 cases were included in our systematic review. The pathogen was most frequently reported in disseminated infections in Spain (n = 47), Australia (n = 33), the USA (n = 21), and Germany (n = 10). Among 142 reported cases, 48.5% were males. Underlying conditions identified for the majority of patients included malignancy (72.5%), hemopoietic stem cell transplantation (23.2%), solid organ transplantation (16%), and AIDS (2%). Lungs, central nervous system, skin, eyes, heart and bones/joints were the most commonly affected organs. Neutropenia was recorded in 52% of patients. The mortality rate was as high as 87.3%.
Conclusions:
To the best of our knowledge, this is the first systematic review conducted on disseminated infections due to this rare microorganism. Physicians should be aware that L. prolificans can cause a diversity of infections with high mortality and primarily affects immunocompromised and neutropenic patients.
... In addition to their therapy-refractory nature, the treatment of infections caused by these species is impinged by their nocuous virulent features that lead to irreparable harm to invaded tissues. This includes the presence of cell wall components with immunomodulatory effects, the secretion of proteins and metabolites that promote the ability to establish infections, and the attitude of the fungus toward the stressful conditions imposed in the host [6][7][8]. In this regard, and since the release of the first whole-genome sequencing of S. apiospermum [9], special attention has been paid to the antioxidant repertoire that permits the fungus to modulate host-imposed oxidative stress. ...
Scedosporium species are opportunistic filamentous fungi found in human-impacted areas. Clinically relevant species, such as S. apiospermum, rank as the second most frequent colonizers of the airways of patients with cystic fibrosis (CF), which are characterized by persistent oxidative stress. This raises the question of how Scedosporium species abate conditions imposed in hostile environments. Since the High Osmolarity Glycerol (HOG) pathway plays a central role in fungal adaptation to stress, we aimed to pheno-profile the involvement of the pathway in response to stress in S. apiospermum using Western blot. We show for the first time that a wide range of stress distinctively activates the HOG pathway in S. apiospermum, including oxidants (H2O2, menadione, cumene hydroperoxide, diamide, paraquat, and honokiol), osmotic agents (sorbitol and KCl), cell-wall stress agents (caffeine, calcofluor white, and Congo Red), heavy metals (cadmium and arsenite), fungicides (fludioxonil and iprodione), antifungals (voriconazole and amphotericin B), and acid stress (pH 4). We suggest that the function of the HOG pathway as a general stress regulator is also conserved in S. apiospermum
... Potential virulence factors in the fungal cell wall involved in important biological events include peptidorhamnomannan, glucosylceramide, and melanin [26]. Peptidorhamnomannan, especially the O-glycosides of the molecule, is a key determinant for fungal recognition and phagocytosis, and induces killing by macrophages and production of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), and nitric oxide (NO) [27]. ...
... Peptidorhamnomannan, especially the O-glycosides of the molecule, is a key determinant for fungal recognition and phagocytosis, and induces killing by macrophages and production of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), and nitric oxide (NO) [27]. Another bioactive molecule present on the surface of conidial and hyphal cells is glucosylceramide (GLcCer) [26]. GLcCer belongs to sphingolipids, which are essential for fungal growth, virulence, and hyphal elongation. ...
... Explicitly, purified GLcCer from L. prolificans activates peritoneal macrophages, leading to the production of NO and superoxide and, consequently, to conidial death [28]. Moreover, in vivo experiments have shown that purified GLcCer from L. prolificans was able to increase the production of pro-inflammatory cytokines by splenocytes and induce recruitment of PMNs, eosinophils, small peritoneal macrophages, and mononuclear cells to the peritoneal cavity [26,28]. However, the receptor of GLcCer has not yet been discovered. ...
Lomentospora prolificans is an emerging opportunistic pathogen that primarily affects immunocompromised individuals leading to disseminated disease with high mortality rates while also causing infections in healthy populations. Successful recovery from infection is difficult due to high rates of intrinsic resistance to antifungals. Rapid and readily available diagnostic methods, aggressive surgical debridement wherever appropriate, and effective and timely antifungal treatment are the pillars for successful management. Future research will need to clarify the environmental niche of the fungus, further investigate the pathophysiology of infection and define species-specific therapeutic targets.
... In the last decade, a growing importance has been given to the impact of structural data on specific cell wall glycoconjugates present on the surface of fungal pathogens and the host immune response to each genus and/or species (22). These studies require an overlap of biochemical and ultrastructural data of a cell wall component and knowledge on the crosstalk with specific PRRs of host cells and its impact on the host immune response (22,(55)(56)(57)(58). The fungal cell wall is composed of 80% sugars and, in general, the glycoproteins are present on the outermost microfibrillar layer of the cell wall of yeasts as proposed for Candida albicans (59). ...
... The mannan structure in mannoproteins of Candida species is the best known among fungal pathogens (60). In contrast, rhamnomannans are unique structures found on the cell wall of Sporothrix and Scedosporium species (31,46,58), and data on their role on the host immune response are still scarce (58). ...
... The mannan structure in mannoproteins of Candida species is the best known among fungal pathogens (60). In contrast, rhamnomannans are unique structures found on the cell wall of Sporothrix and Scedosporium species (31,46,58), and data on their role on the host immune response are still scarce (58). ...
In this study, the human immune response mechanisms against Sporothrix brasiliensis and Sporothrix schenckii , two causative agents of human and animal sporotrichosis, were investigated. The interaction of S. brasiliensis and S. schenckii with human monocyte-derived macrophages (hMDMs) was shown to be dependent on the thermolabile serum complement protein C3, which facilitated the phagocytosis of Sporothrix yeast cells through opsonization. The peptidorhamnomannan (PRM) component of the cell walls of these two Sporothrix yeasts was found to be one of their surfaces exposed pathogen-associated molecular pattern (PAMP), leading to activation of the complement system and deposition of C3b on the Sporothrix yeast surfaces. PRM also showed direct interaction with CD11b, the specific component of the complement receptor-3 (CR3). Furthermore, the blockade of CR3 specifically impacted the interleukin (IL)-1β secretion by hMDM in response to both S. brasiliensis and S. schenckii , suggesting that the host complement system plays an essential role in the inflammatory immune response against these Sporothrix species. Nevertheless, the structural differences in the PRMs of the two Sporothrix species, as revealed by NMR, were related to the differences observed in the host complement activation pathways. Together, this work reports a new PAMP of the cell surface of pathogenic fungi playing a role through the activation of complement system and via CR3 receptor mediating an inflammatory response to Sporothrix species.
... Calcofluor White is known to bind to chitin, whereas Congo red may also interfere with glucans as described in S. cerevisiae [73]. Contrasting with other fungi, glucans have been detected in the cell wall of Scedosporium species, but mainly alpha-glucans and only a low level of beta-glucans [74]. Nevertheless, the increased susceptibility to Congo red resulting from disruption of the SODD gene suggests a defect in cell wall integrity. ...
Scedosporium species are common fungal pathogens in patients with cystic fibrosis (CF). To colonize the CF lungs, fungi must cope with the host immune response, especially the reactive oxygen species (ROS) released by phagocytic cells. To this aim, pathogens have developed various antioxidant systems, including superoxide dismutases (SODs) which constitute the first-line protection against oxidative stress. Interestingly, one of the S. apiospermum SOD-encoding genes (SODD gene) exhibits a glycosylphosphatidylinositol (GPI) anchor-binding site and encodes a conidial-specific surface SOD. In this study, a SODDΔ mutant was engineered from a non-homologous end joining-deficient strain (KU70Δ) of S. apiospermum. Compared to its parent strain, the double mutant KU70Δ/SODDΔ exhibited increased susceptibility to various oxidizing agents and triazole antifungals. In addition, the loss of SodD resulted in an increased intracellular killing of the conidia by M1 macrophages derived from human blood monocytes, suggesting the involvement of this superoxide dismutase in the evasion to the host defenses. Nevertheless, one cannot disregard an indirect role of the enzyme in the synthesis or assembly of the cell wall components since transmission electron microscopic analysis revealed a thickening of the inner cell wall layer of the conidia. Further studies are needed to confirm the role of this enzyme in the pathogenesis of Scedosporium infections, including the production of a recombinant protein and study of its protective effect against the infection in a mouse model of scedosporiosis.
... Glycoconjugates from the fungal surface are essential for fungal viability, morphogenesis and pathogenesis. Therefore, these molecules represent important new targets for antifungal therapy (Gow et al., 2017;Rollin-Pinheiro et al., 2020). In this context, glucosylceramide (GlcCer) is the main sphingolipid present in the fungal cell wall and membrane (Barreto-Bergter et al., 2011). ...
Scedosporium and Lomentospora species are filamentous fungi responsible for a wide range of infections in humans and are frequently associated with cystic fibrosis and immunocompromising conditions. Because they are usually resistant to many antifungal drugs available in clinical settings, studies of alternative targets in fungal cells and therapeutic approaches are necessary. In the present work, we evaluated the in vitro antifungal activity of miltefosine against Scedosporium and Lomentospora species and how this phospholipid analogue affects the fungal cell. Miltefosine inhibited different Scedosporium and Lomentospora species at 2–4 µg/ml and reduced biofilm formation. The loss of membrane integrity in Scedosporium aurantiacum caused by miltefosine was demonstrated by leakage of intracellular components and lipid raft disorganisation. The exogenous addition of glucosylceramide decreased the inhibitory activity of miltefosine. Reactive oxygen species production and mitochondrial activity were also affected by miltefosine, as well as the susceptibility to fluconazole, caspofungin and myoricin. The data obtained in the present study contribute to clarify the dynamics of the interaction between miltefosine and Scedosporium and Lomentospora cells, highlighting its potential use as new antifungal drug in the future.
... On the other hand, glucosylceramide (GlcCer) has been described as a potent immune response activator present on the Scedosporium/Lomentospora conidial and hyphal cell surface [55]. Specifically, purified GlcCer from S. aurantiacum and L. prolificans leads to peritoneal macrophage activation, inducing NO and superoxide production and increasing the killing of L. prolificans conidia [56,57]. ...
... Specifically, purified GlcCer from S. aurantiacum and L. prolificans leads to peritoneal macrophage activation, inducing NO and superoxide production and increasing the killing of L. prolificans conidia [56,57]. In addition, in vivo assays have shown that purified GlcCer species from L. prolificans were able to induce a high secretion of pro-inflammatory cytokines by splenocytes, and to promote the recruitment of PMNs, eosinophils, small peritoneal macrophages and mononuclear cells to the peritoneal cavity [55,57]. However, the GlcCer receptor/s have not yet been elucidated. ...
... Moreover, species of Scedosporium/Lomentospora produce 1,8-dihydroxynaphthalene melanin (DHN-melanin), also found in A. fumigatus conidia [116]. This molecule is known to facilitate evasion of immune response by masking PAMPs, by interfering with phagolysosome formation and acidification and by inhibition of host cell apoptotic pathways [55]. However, Scedosporium/Lomentospora melanin function has been poorly studied so far. ...
Infections caused by the opportunistic pathogens Scedosporium/Lomentospora are on the rise. This causes problems in the clinic due to the difficulty in diagnosing and treating them. This review collates information published on immune response against these fungi, since an understanding of the mechanisms involved is of great interest in developing more effective strategies against them. Scedosporium/Lomentospora cell wall components, including peptidorhamnomannans (PRMs), α-glucans and glucosylceramides, are important immune response activators following their recognition by TLR2, TLR4 and Dectin-1 and through receptors that are yet unknown. After recognition, cytokine synthesis and antifungal activity of different phagocytes and epithelial cells is species-specific, highlighting the poor response by microglial cells against L. prolificans. Moreover, a great number of Scedosporium/Lomentospora antigens have been identified, most notably catalase, PRM and Hsp70 for their potential medical applicability. Against host immune response, these fungi contain evasion mechanisms, inducing host non-protective response, masking fungal molecular patterns, destructing host defense proteins and decreasing oxidative killing. In conclusion, although many advances have been made, many aspects remain to be elucidated and more research is necessary to shed light on the immune response to Scedosporium/Lomentospora.
... In fungi, GlcCer has a conserved structure, with minor differences observed in different morphotypes, isolates and species [15]. GlcCer synthesis is performed by the action of a variety of enzymes, which includes a reductase to form 3-ketodihydrosphingosine, a ceramide synthase that adds a fatty acid chain to the sphingoid base, two sequential desaturases that add double bonds at carbons 4 and 8, a methyl transferase which adds the methyl group at carbon 9 and, finally, the GlcCer synthase that brings the sugar unit to the molecule [32]. Studies revealed that ∆8-desaturation and C9-methylation found in fungal GlcCer are not present in mammalian ones, suggesting that genes encoding those desaturase and methyl transferase are absent in mammals [31]. ...
Infections caused by Scedosporium species present a wide range of clinical manifestations, from superficial to disseminated, especially in immunocompromised patients. Glucosylceramides (GlcCer) are glycosphingolipids found on the fungal cell surface and play an important role in growth and pathogenicity processes in different fungi. The present study aimed to evaluate the structure of GlcCer and its role during growth in two S. aurantiacum isolates. Purified GlcCer from both isolates were obtained and its chemical structure identified by mass spectrometry. Using ELISA and immunofluorescence techniques it was observed that germination and NaOH-treatment of conidia favor GlcCer exposure. Monoclonal anti-GlcCer antibody reduced germination when cultivated with the inhibitor of melanin synthesis tricyclazole and also reduced germ tube length of conidia, both cultivated or not with tricyclazole. It was also demonstrated that anti-GlcCer altered lipid rafts organization, as shown by using the fluorescent stain filipin, but did not affect the susceptibility of the cell surface to damaging agents. Anti-GlcCer reduced total biomass and viability in biofilms formed on polystyrene plates. In the presence of anti-GlcCer, germinated S. aurantiacum conidia and biofilms could not adhere to polystyrene with the same efficacy as control cells. These results highlight the relevance of GlcCer in growth processes of S. aurantiacum.
Although Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.
