Host, pathogenic fungi and the microbiome: A genetic triangle in infection

Abstract

The first perspective: The host geneticsThe outcome of fungal disease is determined by complex interactions between fungal pathogens, human hosts and their environment including the host microbiome (1-4). Morbidity and mortality in fungal disease remain very high despite recent advances in the diagnostic and treatment of these conditions (5-7). There are only three classes of antifungal drugs available to treat these disease and, antifungal resistance linked to the use of agricultural use of triazole fungicides is on the rise (8). The development of new antifungal drugs to treat human fungal disease is challenging as both, host and pathogen are eukaryotes and, there are different potential druggable targets exposed at different points of fungal morphogenesis.So far, the identification of high-risk patients for fungal disease has relied on the use of clinical scores that combine the use of clinical and host factors to predict the risk of subsequent disease (9-11). However, the prevalence of opportunistic fungal diseases within at-risk population, ranges from 0.1 -20% (12). In the last decades, individual genetic variation has been recognised as a major contribution of functional immune responses against fungal pathogens. Several monogenic defects and polymorphisms in genes regulating antifungal immunity or pathogen sensing have been associated with susceptibility to aspergillosis, cryptococcosis and candidiasis (13) (Figure 1).Sensing of human fungal pathogens by the host immune system requires the interplay between pathogen-associated molecular patterns (PAMPs), mostly located in the cell wall of fungal pathogens, and pattern recognition receptors (PRRs) (14-17). The interaction between PRRs and PAMPs, leads to the regulation of uptake of fungal pathogens by immune cells. In addition to membrane receptors, soluble PRRs such as pentraxins or mannose binding lectins (MBLs) are also critical for pathogen sensing and efficient phagocytosis (18, 19).To date, polymorphisms in PTX3 have been reported in different clinical settings as a risk factor for invasive pulmonary aspergillosis in haematopoietic stem cell transplant recipients (20), solid organ transplants (21) and chronic obstructive pulmonary disease (22). Using ex Frontiers in Immunology frontiersin.org 01