Abstract
Elucidation of pathogenicity mechanisms of the most important human-pathogenic fungi, Aspergillus fumigatus and Candida albicans, has gained great interest in the light of the steadily increasing number of cases of invasive fungal infections. A key feature of these infections is the interaction of the different fungal morphotypes with epithelial and immune effector cells in the human host. Because of the high level of complexity, it is necessary to describe and understand invasive fungal infection by taking a systems biological approach, i.e., by a comprehensive quantitative analysis of the non-linear and selective interactions of a large number of functionally diverse, and frequently multifunctional, sets of elements, e.g., genes, proteins, metabolites, which produce coherent and emergent behaviors in time and space. The recent advances in systems biology will now make it possible to uncover the structure and dynamics of molecular and cellular cause-effect relationships within these pathogenic interactions. We review current efforts to integrate omics and image-based data of host-pathogen interactions into network and spatio-temporal models. The modeling will help to elucidate pathogenicity mechanisms and to identify diagnostic biomarkers and potential drug targets for therapy and could thus pave the way for novel intervention strategies based on novel antifungal drugs and cell therapy.
Highlights
Despite the different pathogenesis of infections caused by C. albicans and A. fumigatus, there are several common traits, when the host response is considered: (i) the pathogens must be able to overcome epithelial barriers, (ii) innate immunity represents the major defense system, (iii) pathogenic fungi possess physiological characteristics, virulence determinants, and capabilities for immune evasion that make them aggressive pathogens, and (iv) invasive candidiasis and invasive aspergillosis are mainly found in patients with a weakened immune system either due to reduced activity of immune effector cells or defects in epithelial barriers
Phagocytosis of conidia by dendritic cells (DCs) leads to a protective Th1 response, whereas hyphal phagocytosis results in non-favorable Th2 responses and the generation of IL-10-producing CD4 cells (Romani, 2011)
After establishing protocols for targeted gene disruptions of both alleles, creating conditional null mutants based on tetracycline-regulatable systems, sequencing of the entire genome, establishment of a genome database, production of genome-wide microarrays, and production of reporter strains and other molecular tools as well as infection models, has C. albicans reached the status of a model organism for yeast infections (Theiss et al, 2002; Fradin et al, 2003; Jones et al, 2004; Braun et al, 2005; Samaranayake and Hanes, 2011; Szabo and MacCallum, 2011)
Summary
Despite the different pathogenesis of infections caused by C. albicans and A. fumigatus, there are several common traits, when the host response is considered: (i) the pathogens must be able to overcome epithelial barriers, (ii) innate immunity represents the major defense system, (iii) pathogenic fungi possess physiological characteristics, virulence determinants, and capabilities for immune evasion that make them aggressive pathogens, and (iv) invasive candidiasis and invasive aspergillosis are mainly found in patients with a weakened immune system either due to reduced activity of immune effector cells or defects in epithelial barriers. A. fumigatus causes 90% of all systemic Aspergillus infections This indicates that A. fumigatus possesses certain virulence determinants that favor this species becoming an opportunistic human pathogen. Phagocytosis of conidia by DCs leads to a protective Th1 response, whereas hyphal phagocytosis results in non-favorable Th2 responses and the generation of IL-10-producing CD4 cells (Romani, 2011)
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