bioRxiv - the Preprint Server for Biology.C. neoformans is notorious for causing severe pulmonary and central nervous system infections, particularly in immunocompromised patients. High mortality rates, associated with its tropism and adaptation to the brain microenvironment and its drug resistance profile, makes this pathogen a public health threat and a World Health Organization (WHO) priority.In this study, we reconstructed GSMM iRV890 for C. neoformans var. grubii, providing a promising platform for the comprehensive understanding of the unique metabolic features of C. neoformans, and subsequently shedding light on its complex tropism for the brain microenvironment and potentially informing the discovery of new drug targets. The GSMM iRV890 model is openly available in the SBML format, and underwent validation using experimental data for nitrogen and carbon assimilation, as well as specific growth and glucose consumption rates. Based on the comparison with GSMMs available for other pathogenic yeasts, unique metabolic features were predicted for C. neoformans, including key pathways shaping the dynamics between C. neoformans and the human host, and underlying its adaptation to the brain environment. Finally, predicted essential genes from the validated model are explored herein as potential novel antifungal drug targets.The authors acknowledge the OSCARS project, funded by the European Commission’s Horizon Europe Research and Innovation Programme under grant agreement No. 101129751. This work was further financed by national funds from “Fundação para a Ciência e a Tecnologia” (FCT) (AEM PhD grant to RV; projects UIDB/04565/2020 and UIDP/04565/2020 of the Research Unit Institute for Bioengineering and Biosciences—iBB; project UIDB/04469/2020 for the Centre of Biological Engineering—CEB; project LA/P/0029/2020 for LABBELS –Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems; and project LA/P/0140/2020 for the Associate Laboratory Institute for Health and Bioeconomy—i4HB). WN was funded by a DTP BRC Exeter NIHR203320. Fungal strain collection was funded via NIH funding (R01AI100272) led by Hiten Madhani, UCSF. This work was supported by AMS Springboard Award SBF006\1024 (UK), and Wellcome Trust Institutional Strategic Support Award (WT105618MA) to C.C. We acknowledge other funding from the MRC Centre for Medical Mycology at the University of Exeter (MR/N006364/2 and MR/V033417/1). This study/research is funded by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.info:eu-repo/semantics/publishedVersio
