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Background A major outbreak of COVID19-associated mucormycosis (CAM) in India in spring 2021 aggravated the death toll of COVID19. As the causes of that CAM outbreak remain unclear, we performed a multifaceted study of host, pathogen, environmental, and heath care-related factors in adult CAM patients (pts) in the metropolitan New Delhi area. Methods We reviewed the records of all pts diagnosed with culture- or biopsy-proven CAM at 7 hospitals in the New Delhi area (April 1 – June 30, 2021). We used a multivariate logistic regression model to compare clinical characteristics of either all CAM cases (analysis 1, n = 50) or only pts with CAM after moderate or severe COVID19 (analysis 2, n = 31). As controls for both analyses, we used 69 COVID19-hospitalized contemporary pts. Selected hospital fomites were cultured for Mucorales. Additionally, we compared meteorological data and fungal spore concentrations in outdoor air before the CAM outbreak (January-March 2021) and during the outbreak (April-June 2021). Mucorales isolates from CAM pts were identified by MALDI-TOF-MS and ITS sequencing. A subset of 15 isolates underwent whole genome sequencing (WGS). Results Risk factors for CAM in both analyses were newly diagnosed diabetes mellitus (odds ratio [OR] 8.26/5.67) and active cancer (OR 5.98/5.68) (Figure 1). Supplemental oxygen for COVID19 was associated with a lower CAM risk in both analyses (OR 0.13/0.17). Another significant CAM risk predictor identified only in analysis 1 was severe COVID19 (WHO score ≥ 6, OR 4.09), while remdesivir therapy (OR 0.40) and ICU admission for COVID19 were protective (OR 0.41) (Figure 1). No Mucorales were cultured from hospital fomites. The CAM incidence peak coincided with a significant uptick in environmental spore concentrations but was not linked to specific meteorological factors. Rhizopus was the predominant Mucorales genus (64%) identified by MALDI-TOF-MS and ITS sequencing; WGS found no clonal population of isolates but detected 2 cases of the rare pathogen Lichtheimia ornata. Figure 1 Conclusion An intersection of host, environmental, pathogen and healthcare-related factors might have contributed to the emergence of CAM. Surrogates of access to advanced treatment of COVID19 were associated with lower CAM risk. Disclosures Dimiitrios P. Kontoyiannis, MD, ScD, PhD (hon), AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant.

The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation. To address this aim, the Canadian Institute for Advanced Research (CIFAR) and the Burroughs Wellcome Fund convened a workshop to unite leading experts on fungal biology from academia and industry to strategize innovative solutions to global challenges and fungal threats. This report provides recommendations to accelerate fungal research and highlights the major research advances and ideas discussed at the meeting pertaining to 5 major topics: (1) Connections between fungi and climate change and ways to avert climate catastrophe; (2) Fungal threats to humans and ways to mitigate them; (3) Fungal threats to agriculture and food security and approaches to ensure a robust global food supply; (4) Fungal threats to animals and approaches to avoid species collapse and extinction; and (5) Opportunities presented by the fungal kingdom, including novel medicines and enzymes.

Fungi survive in diverse ecological niches by secreting proteins and other molecules into the environment to acquire food and interact with various biotic and abiotic stressors. Fungal secretome content is, therefore, believed to be tightly linked to fungal ecologies. We sampled 132 genomes from the early-diverging terrestrial fungal lineage zygomycetes (Mucoromycota and Zoopagomycota) and characterized their secretome composition. Our analyses revealed that phylogeny played an important role in shaping the secretome composition of zygomycete fungi with trophic mode contributing a smaller amount. Reconstruction of the evolution of secreted digestive enzymes revealed lineage-specific expansions, indicating that Mucoromycota and Zoopagomycota followed different trajectories early in their evolutionary history. We identified the presence of multiple pathogenicity-related proteins in the lineages known as saprotrophs, suggesting that either the ecologies of these fungi are incompletely known, and/or that these pathogenicity-related proteins have important functions associated with saprotrophic ecologies, both of which invite further investigation.

The rise in drug resistance amongst pathogenic fungi, paired with the limited arsenal of antifungals available is an imminent threat to our medical system. To address this, we screened two distinct compound libraries to identify novel strategies to expand the antifungal armamentarium. The first collection wasthe RIKEN Natural Product Depository (NPDepo), which was screened for antifungal activity against four major human fungal pathogens: Candida albicans, Candida glabrata, Candida auris, and Cryptococcus neoformans. Through a prioritization pipeline, one compound, NPD6433, emerged as having broad-spectrum antifungal activity and minimal mammalian cytotoxicity. Chemical-genetic and biochemical assays demonstrated that NPD6433 inhibits the essential fungal enzyme fatty acid synthase 1 (Fas1). Treatment with NPD6433 inhibited various virulence traits in C. neoformans and C. auris, and rescued mammalian cell growth in a co-culture model with C. auris. The second compound library screened was adiversity-oriented collectionfrom Boston University. This chemical screen was focused on identifying novel molecules that enhance the activity of the widely deployed antifungal, fluconazole, against C. auris. Through this endeavour, we discovered a potent compound that enhanced fluconazole efficacy against C. auris through increasing azole intracellular accumulation. This activity was dependent on expression of the multidrug transporter geneCDR1, suggesting that this compound targets efflux mechanisms. Furthermore, this molecule significantly reduced fungal burden alone and in combination with fluconazole in a murine model of C. auris disseminated infection. Overall, this work identifies novel compounds with bioactivity against fungal pathogens, revealing important biology, and paving the way for the critical development of therapeutic strategies.

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.

CandidaDB: http://genodb.pasteur.fr/CandidaDB; International audience; CandidaDB (http://genodb.pasteur.fr/CandidaDB) was established in 2002 to provide the first genomic database for the human fungal pathogen Candida albicans. The availability of an increasing number of fully or partially completed genome sequences of related fungal species has opened the path for comparative genomics and prompted us to migrate CandidaDB into a multi-genome database. The new version of CandidaDB houses the latest versions of the genomes of C. albicans strains SC5314 and WO-1 along with six genome sequences from species closely related to C. albicans that all belong to the CTG clade of Saccharomycotina-Candida tropicalis, Candida (Clavispora) lusitaniae, Candida (Pichia) guillermondii, Lodderomyces elongisporus, Debaryomyces hansenii, Pichia stipitis-and the reference Saccharomyces cerevisiae genome. CandidaDB includes sequences coding for 54 170 proteins with annotations collected from other databases, enriched with illustrations of structural features and functional domains and data of comparative analyses. In order to take advantage of the integration of multiple genomes in a unique database, new tools using pre-calculated or user-defined comparisons have been implemented that allow rapid access to comparative analysis at the genomic scale.