The epidemiology of invasive fungal infections in transplant recipients.

Transplant patients, including solid-organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, are exposed to various types of complications, particularly rejection. To prevent these outcomes, transplant recipients commonly receive long-term immunosuppressive regimens that in turn make them more susceptible to a wide array of infectious diseases, notably those caused by opportunistic pathogens. Among these, invasive fungal infections (IFIs) remain a major cause of mortality and morbidity in both SOT and HSCT recipients. Despite the continuing improvement in early diagnostics and treatments of IFIs, the management of these infections in transplant patients is still complicated. Here, we provide an overview concerning the most recent trends in the epidemiology of IFIs in SOT and HSCT recipients by describing the prominent yeast and mold species involved, the timing of post-transplant IFIs and the risk factors associated with their occurrence in these particularly weak populations. We also give special emphasis into basic research advances in the field that recently suggested a role of the global and long-term prophylactic regimen in orchestrating various biological disturbances in the organism and conditioning the emergence of the most adapted fungal strains to the particular physiological profiles of transplant patients.

The Madagascar palm genome provides new insights on the evolution of Apocynaceae specialized metabolism.

Specialized metabolites possess diverse interesting biological activities and some cardenolides- and monoterpene indole alkaloids- (MIAs) derived pharmaceuticals are currently used to treat human diseases such as cancers or hypertension. While these two families of biocompounds are produced by specific subfamilies of Apocynaceae, one member of this medicinal plant family, the succulent tree Pachypodium lamerei Drake (also known as Madagascar palm), does not produce such specialized metabolites. To explore the evolutionary paths that have led to the emergence and loss of cardenolide and MIA biosynthesis in Apocynaceae, we sequenced and assembled the P. lamerei genome by combining Oxford Nanopore Technologies long-reads and Illumina short-reads. Phylogenomics revealed that, among the Apocynaceae whose genomes have been sequenced, the Madagascar palm is so far the species closest to the common ancestor between MIA producers/non-MIA producers. Transposable elements, constituting 72.48% of the genome, emerge as potential key players in shaping genomic architecture and influencing specialized metabolic pathways. The absence of crucial MIA biosynthetic genes such as strictosidine synthase in P. lamerei and non-Rauvolfioideae species hints at a transposon-mediated mechanism behind gene loss. Phylogenetic analysis not only showcases the evolutionary divergence of specialized metabolite biosynthesis within Apocynaceae but also underscores the role of transposable elements in this intricate process. Moreover, we shed light on the low conservation of enzymes involved in the final stages of MIA biosynthesis in the distinct MIA-producing plant families, inferring independent gains of these specialized enzymes along the evolution of these medicinal plant clades. Overall, this study marks a leap forward in understanding the genomic dynamics underpinning the evolution of specialized metabolites biosynthesis in the Apocynaceae family, with transposons emerging as potential architects of genomics restructuring and gene loss.

Functional insights into human macrophage response against Scedosporium apiospermum and Scedosporium dehoogii.

Fungal infections caused by Scedosporium species are rising among immunocompromised and immunocompetent patients. Within the immunocompetent group, patients with cystic fibrosis (pwCF) are at high risk of developing a chronic airway colonization by these molds. While S. apiospermum is one of the major species encountered in the lungs of pwCF, S. dehoogii has rarely been reported. The innate immune response is believed to be critical for host defense against fungal infections. However, its role has only recently been elucidated and the immune mechanisms against Scedosporium species are currently unknown. In this context, we undertook a comparative investigation of macrophage-mediated immune responses toward S. apiospermum and S. dehoogii conidia. Our data showed that S. apiospermum and S. dehoogii conidia strongly stimulated the expression of a set of pro-inflammatory cytokines and chemokines such as IL-1ß, IL-8, IL-6 and TNFα. We demonstrated that S. dehoogii was more potent in stimulating the early release of pro-inflammatory cytokines and chemokines while S. apiospermum induced a late inflammatory response at a higher level. Flow cytometry analysis showed that M1-like macrophages were able to internalize both S. apiospermum and S. dehoogii conidia, with a similar intracellular killing rate for both species. In conclusion, these results suggest that M1-like macrophages can rapidly initiate a strong immune response against both S. apiospermum and S. dehoogii. This response is characterized by a similar killing of internalized conidia, but a different time course of cytokine production.

Are Histidine Kinases of Arbuscular Mycorrhizal Fungi Involved in the Response to Ethylene and Cytokinins?

Signals are exchanged at all stages of the arbuscular mycorrhizal (AM) symbiosis between fungi and their host plants. Root-exuded strigolactones are well-known early symbiotic cues, but the role of other phytohormones as interkingdom signals has seldom been investigated. Here we focus on ethylene and cytokinins, for which candidate receptors have been identified in the genome of the AM fungus Rhizophagus irregularis. Ethylene is known from the literature to affect asymbiotic development of AM fungi, and in the present study, we found that three cytokinin forms could stimulate spore germination in R. irregularis. Heterologous complementation of a Saccharomyces cerevisiae mutant strain with the candidate ethylene receptor RiHHK6 suggested that this protein can sense and transduce an ethylene signal. Accordingly, its N-terminal domain expressed in Pichia pastoris displayed saturable binding to radiolabeled ethylene. Thus, RiHHK6 displays the expected characteristics of an ethylene receptor. In contrast, the candidate cytokinin receptor RiHHK7 did not complement the S. cerevisiae mutant strain or Medicago truncatula cytokinin receptor mutants and seemed unable to bind cytokinins, suggesting that another receptor is involved in the perception of these phytohormones. Taken together, our results support the hypothesis that AM fungi respond to a range of phytohormones and that these compounds bear multiple functions in the rhizosphere beyond their known roles as internal plant developmental regulators. Our analysis of two phytohormone receptor candidates also sheds new light on the possible perception mechanisms in AM fungi. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Airway microbiome: environmental exposure-respiratory health nexus.

Toxicants such as smoke, biofuel, and pollutants constantly challenge our respiratory health, but little is known about the pathophysiological processes involved. In a new report, Lin et al. provide evidence that our bacterial and fungal lung populations orchestrate the interplay between environmental exposure and lung functions, thereby conditioning health outcomes.

Medicinal plants enter the single-cell multi-omics era.

Elucidating biosynthetic pathways of plant specialized metabolites is a tricky but essential task for the biotechnological production of plant drugs. In a new report, Li et al. used a single-cell multi-omics approach to provide an integrative view of the architecture and regulation of anticancer alkaloid routes in Madagascar periwinkle.

The Evolutionary Pattern of Cocaine and Hyoscyamine Biosynthesis Provides Strategies To Produce Tropane Alkaloids.

Cocaine and hyoscyamine are two tropane alkaloids (TA) from Erythroxylaceae and Solanaceae, respectively. These famous compounds possess anticholinergic properties that can be used to treat neuromuscular disorders. While the hyoscyamine biosynthetic pathway has been fully elucidated allowing its de novo synthesis in yeast, the cocaine pathway remained only partially elucidated. Recently, the Huang research group has completed the cocaine biosynthetic route by characterizing its two missing enzymes. This allowed the whole pathway to be transferring into Nicotiana benthamiana to achieve cocaine production. Here, besides highlighting the impact of this discovery, we discuss how TA biosynthesis evolved via the recruitment of two distinct and convergent pathways in Erythroxylaceae and Solanaceae. Finally, while enriching our knowledge on TA biosynthesis, this diversification of the molecular actors involved in cocaine and hyoscyamine biosynthesis opens perspectives in metabolic engineering by exploring enzyme biochemical plasticity that can ease and shorten TA pathway reconstitution in heterologous organisms.

Identification of a second 16-hydroxytabersonine-O-methyltransferase suggests an evolutionary relationship between alkaloid and flavonoid metabolisms in Catharanthus roseus.

The medicinal plant Catharanthus roseus biosynthesizes many important drugs for human health, including the anticancer monoterpene indole alkaloids (MIAs) vinblastine and vincristine. Over the past decades, the continuous increase in pharmaceutical demand has prompted several research groups to characterize MIA biosynthetic pathways for considering future metabolic engineering processes of supply. In line with previous work suggesting that diversification can potentially occur at various steps along the vindoline branch, we were here interested in investigating the involvement of distinct isoforms of tabersonine-16-O-methyltransferase (16OMT) which plays a pivotal role in the MIA biosynthetic pathway. By combining homology searches based on the previously characterized 16OMT1, phylogenetic analyses, functional assays in yeast, and biochemical and in planta characterizations, we identified a second isoform of 16OMT, referred to as 16OMT2. 16OMT2 appears to be a multifunctional enzyme working on both MIA and flavonoid substrates, suggesting that a constrained evolution of the enzyme for accommodating the MIA substrate has probably occurred to favor the apparition of 16OMT2 from an ancestral specific flavonoid-O-methyltransferase. Since 16OMT1 and 16OMT2 displays a high sequence identity and similar kinetic parameters for 16-hydroxytabersonine, we postulate that 16OMT1 may result from a later 16OMT2 gene duplication accompanied by a continuous neofunctionalization leading to an almost complete loss of flavonoid O-methyltransferase activity. Overall, these results participate in increasing our knowledge on the evolutionary processes that have likely led to enzyme co-optation for MIA synthesis.

Central Sugar Metabolism and the Cell Wall.

The human opportunistic pathogen Aspergillus fumigatus is recognized for its versatile cell wall when it comes to remodeling its components in adaptation to external threats, and this remodeling renders it refractory to antifungals targeting cell wall biosynthesis. A specific role for general sugar metabolism in the regulation of the synthesis of cell wall polymers has been previously demonstrated. Delving deeper into central sugar metabolism may reveal unexpected fundamental aspects in cell wall construction, as shown by the work of Zhou and coworkers (Y. Zhou, K. Yan, Q. Qin, O.G. Raimi, et al., mBio 13:e01426-22, 2022, https://doi.org/10.1128/mbio.01426-22) on the roles of the phosphoglucose isomerase of A. fumigatus in cell wall biosynthesis.

Marine drugs: Biology, pipelines, current and future prospects for production.

The marine environment is a huge reservoir of biodiversity and represents an excellent source of chemical compounds, some of which have large economical values. In the urgent quest for new pharmaceuticals, marine-based drug discovery has progressed significantly over the past several decades and we now benefit from a series of approved marine natural products (MNPs) to treat cancer and pain while an additional collection of promising leads are in clinical trials. However, the discovery and supply of MNPs has always been challenging given their low bioavailability and structural complexity. Their manufacture for pre-clinical and clinical development but also commercialization mainly relies upon marine source extraction and chemical synthesis, which are associated with high costs, unsustainability and severe environmental problems. In this review, we discuss how metabolic engineering now raises reasonable expectations for the implementation of microbial cell factories, which may provide a sustainable approach for MNP-based drug supply in the near future.

An updated version of the Madagascar periwinkle genome.

The Madagascar periwinkle, Catharanthus roseus, belongs to the Apocynaceae family. This medicinal plant, endemic to Madagascar, produces many important drugs including the monoterpene indole alkaloids (MIA) vincristine and vinblastine used to treat cancer worldwide. Here, we provide a new version of the C. roseus genome sequence obtained through the combination of Oxford Nanopore Technologies long-reads and Illumina short-reads. This more contiguous assembly consists of 173 scaffolds with a total length of 581.128 Mb and an N50 of 12.241 Mb. Using publicly available RNAseq data, 21,061 protein coding genes were predicted and functionally annotated. A total of 42.87% of the genome was annotated as transposable elements, most of them being long-terminal repeats. Together with the increasing access to MIA-producing plant genomes, this updated version should ease evolutionary studies leading to a better understanding of MIA biosynthetic pathway evolution.

Smoking-aggravated oral candidiasis: Nrf2 pathway dampens NLRP3 inflammasome.

While cigarette smoke compounds are known to have immunosuppressive effects on the oral mucosa, the relationship between in vivo immune dysfunction caused by smoking and the development of oral Candida infections remains largely unexplored. In a recent issue of The Journal of Cellular and Molecular Medicine, Ye and colleagues provide evidence that smoking increases oral mucosa susceptibility to Candida albicans infection via the activation of the Nrf2 pathway, which in turn negatively regulates the NLRP3 inflammasome. This opens new perspective in considering Nrf2 as a relevant target for smoking-induced C. albicans-related oral diseases.

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories.

Plant specialized metabolites are widely used in the pharmaceutical industry, including the monoterpene indole alkaloids (MIAs) vinblastine and vincristine, which both display anticancer activity. Both compounds can be obtained through the chemical condensation of their precursors vindoline and catharanthine extracted from leaves of the Madagascar periwinkle. However, the extensive use of these molecules in chemotherapy increases precursor demand and results in recurrent shortages, explaining why the development of alternative production approaches, such microbial cell factories, is mandatory. In this context, the precursor-directed biosynthesis of vindoline from tabersonine in yeast-expressing heterologous biosynthetic genes is of particular interest but has not reached high production scales to date. To circumvent production bottlenecks, the metabolic flux was channeled towards the MIA of interest by modulating the copy number of the first two genes of the vindoline biosynthetic pathway, namely tabersonine 16-hydroxylase and tabersonine-16-O-methyltransferase. Increasing gene copies resulted in an optimized methoxylation of tabersonine and overcame the competition for tabersonine access with the third enzyme of the pathway, tabersonine 3-oxygenase, which exhibits a high substrate promiscuity. Through this approach, we successfully created a yeast strain that produces the fourth biosynthetic intermediate of vindoline without accumulation of other intermediates or undesired side-products. This optimization will probably pave the way towards the future development of yeast cell factories to produce vindoline at an industrial scale.

Enhanced bioproduction of anticancer precursor vindoline by yeast cell factories.

The pharmaceutical industry faces a growing demand and recurrent shortages in many anticancer plant drugs given their extensive use in human chemotherapy. Efficient alternative strategies of supply of these natural products such as bioproduction by microorganisms are needed to ensure stable and massive manufacturing. Here, we developed and optimized yeast cell factories efficiently converting tabersonine to vindoline, a precursor of the major anticancer alkaloids vinblastine and vincristine. First, fine-tuning of heterologous gene copies restrained side metabolites synthesis towards vindoline production. Tabersonine to vindoline bioconversion was further enhanced through a rational medium optimization (pH, composition) and a sequential feeding strategy. Finally, a vindoline titre of 266 mg l-1 (88% yield) was reached in an optimized fed-batch bioreactor. This precursor-directed synthesis of vindoline thus paves the way towards future industrial bioproduction through the valorization of abundant tabersonine resources.

Computational biotechnology guides elucidation of the biosynthesis of the plant anticancer drug camptothecin.

Camptothecin is a clinically important monoterpene indole alkaloid (MIAs) used for treating various cancers. Currently, the production of this biopharmaceutical hinges on its extraction from camptothecin-producing plants, leading to high market prices and supply bottlenecks. While synthetic biology combined with metabolic approaches could represent an attractive alternative approach to manufacturing, it requires firstly a complete biosynthetic pathway elucidation, which is, unfortunately, severely missing in species naturally accumulating camptothecin. This knowledge gap can be attributed to the lack of high-quality genomic resources of medicinal plant species. In such a perspective, Yamazaki and colleagues produced the first described and experimentally validated chromosome-level plant genome assembly of Ophiorrhiza pumila, a prominent source plant of camptothecin for the pharmaceutical industry. More specifically, they have developed a method incorporating Illumina reads, PacBio single-molecule reads, optical mapping and Hi-C sequencing, followed by the experimental validation of contig orientation within scaffolds, using fluorescence in situ hybridization (FISH) analysis. This relevant strategy resulted in the most contiguous and complete de novo plant reference genome described to date, which can streamline the sequencing of new plant genomes. Further mining approaches, including integrative omics analysis, phylogenetics, gene cluster evaluation and comparative genomics were successfully used to puzzle out the evolutionary origins of MIA metabolism and revealed a short-list of high confidence MIA biosynthetic genes for functional validation.

Mycobiota dysbiosis and gastric tumorigenesis.

The gastrointestinal tract contains a vast and diverse microbial reservoir composed of bacteria, fungi, and viruses that contribute positively to human health. There is growing evidence that perturbation of the normal microbiota can promote a variety of human disease states that include tumorigenesis. Whether the fungal component of the gut microbiota (i.e., the mycobiota) can influence tumor development has not been investigated in detail. In the recent issue of the Theranostics, Zhong et al (2021) shed light on an association between mycobiota dysbiosis and gastric cancer. These findings implicate the mycobiota in gastric carcinogenesis and set the stage for future mechanistic studies to explore whether fungal dysbiosis is a cause or consequence of gastric carcinogenesis, with important implications for preventative strategies.

Plant to Insect Horizontal Gene Transfer: Empowering Whiteflies.

Horizontal gene transfer (HGT) is a well-documented evolutionary driving phenomenon in prokaryotes and eukaryotes, but its impact on the plant kingdom has remained elusive. A recent study provides compelling evidences, which support the idea that a plant-derived gene allows for the detoxification of plant defense metabolites in a polyphagous arthropod herbivore.

Repurposing Anticancer Drugs To Tackle Malaria.

Despite considerable efforts, malaria remains one of the most devastating infectious disease worldwide. In the absence of an effective vaccine, the prophylaxis and management of Plasmodium infections still rely on the therapeutic use of antimalarial agents. However, the emergence of resistant parasites has jeopardized the efficiency of virtually all antimalarial drugs, including artemisinin combination therapies (ACTs). Thus, there is an urgent need for innovative treatments with novel targets to avoid or overcome drug resistance. In this context, Huang & colleagues prioritized compounds that can block the activity of epigenetic enzymes, and described the discovery of a selective P. falciparum histone deacetylase (HDAC) inhibitor with high activity against various stages of the parasite. These findings may pave the way toward developing new lead compounds with broad-spectrum activity, thus facilitating malaria treatment and elimination.