A systems genomics approach to identify risk loci and pathways to Candida infection

Candidaemia is a bloodstream yeast infection caused by the opportunistic fungal pathogen Candida albicans (C. albicans). Candida is now ranked the fourth most common cause of nosocomial infections. However, not all at-risk patients will develop fungal disease, suggesting that inter-individual differences – both genetic and non-genetic factors – play a critical role in determining disease susceptibility. However, it is difficult to identify genetic factors using genome-wide association studies alone because of the limited size of candidaemia patient cohorts and use of inappropriate controls (such as individuals with asymptomatic infections). Given the complexity of human host-C. albicans interactions, we followed an integrative approach to obtain a comprehensive picture of these interactions. We integrated multi-omics data (genetics, transcriptomics and proteomics) to identify genes and molecular pathways that are implicated in the anti-Candida host immune response. To generate Candida-specific data in addition to our candidaemia cohort, we made use of larger population-based cohorts (the 500FG and Lifelines cohorts). Our results suggested an important role for the processes of complement and hemostasis in candidaemia susceptibility. In addition, we observed that increased risk to candidaemia could be explained by a disturbed lipid homeostasis, which regulates pro-inflammatory cytokines in response to Candida infection. Although there are still challenges to face before fully embracing genomics in a clinical setting, and challenges to fully unravelling the true risks of disease remain, stratification of patients based on their genetic profile is a promising route toward designing host-directed therapies that would be more effective than the currently available traditional therapeutic approaches