A history of type 2 diabetes results in immune dysregulation and failure to contain a fatal fungal infection

Abstract Glucose metabolism enables antimicrobial defences, but it also contributes to pathogen proliferation and immune evasion. A key disease of glucose metabolism, type 2 diabetes (T2D), leads to worse outcomes of Candida albicans infections with poorly understood mechanisms. Here we used genetic and dietary animal models of T2D and show that, following bloodstream C. albicans infection, T2D animals develop strongly exacerbated disease across several T2D aetiologies. Obesity alone (without overt hyperglycaemia) is sufficient to worsen C. albicans disease, but it does not fully recapitulate the severity in T2D hosts that are both obese and overtly hyperglycaemic. Mechanistic analyses showed that a convergence of pathogen and host factors leads to poor outcomes in T2D. C. albicans exploits poor host glycaemic control through activation of a transcriptional program for glucose utilisation to drive pathogen proliferation. This, combined with dysregulated immunity characterised by increased pro-inflammatory responses and reduced interferon and NK cell signatures, leads to host failure in restricting fungal growth. We further show that life-long metabolic dysregulation, rather than blood glucose levels at infection, drives poor infection outcomes. Our study illuminates host and pathogen mechanisms leading to worse fungal infection in T2D, provides a rich multi-omics resource for understanding fungal infection in metabolic diseases, and suggests that long-term control of metabolic dysregulation, rather than acute lowering of glucose, is essential for improving survival.