Epithelial invasion outcompetes hypha development during Candida albicans infection as revealed by an image‐based systems biology approach

Abstract

Candida albicans is the most common opportunistic fungal pathogen of the human mucosal flora, frequently causing infections. The fungus is responsible for invasive infections in immunocompromised patients that can lead to sepsis. The yeast to hypha transition and invasion of host-tissue represent major determinants in the switch from benign colonizer to invasive pathogen. A comprehensive understanding of the infection process requires analyses at the quantitative level. Utilizing fluorescence microscopy with differential staining, we obtained images of C. albicans undergoing epithelial invasion during a time course of 6 h. An image-based systems biology approach, combining image analysis and mathematical modeling, was applied to quantify the kinetics of hyphae development, hyphal elongation, and epithelial invasion. The automated image analysis facilitates high-throughput screening and provided quantities that allow for the time-resolved characterization of the morphological and invasive state of fungal cells. The interpretation of these data was supported by two mathematical models, a kinetic growth model and a kinetic transition model, that were developed using differential equations. The kinetic growth model describes the increase in hyphal length and revealed that hyphae undergo mass invasion of epithelial cells following primary hypha formation. We also provide evidence that epithelial cells stimulate the production of secondary hyphae by C. albicans. Based on the kinetic transition model, the route of invasion was quantified in the state space of non-invasive and invasive fungal cells depending on their number of hyphae. This analysis revealed that the initiation of hyphae formation represents an ultimate commitment to invasive growth and suggests that in vivo, the yeast to hypha transition must be under exquisitely tight negative regulation to avoid the transition from commensal to pathogen invading the epithelium. V C 2013 International Society for Advancement of Cytometry

A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a

“…This would allow for an accurate mathematical description of the whole-blood model by explicitly accounting for mechanism of PMN activation: 1) time-dependent cleavage and diffusion of C5a and 2) morphological changes of C. albicans. The hyphal growth kinetics can be experimentally determined by an image-based systems biology approach, as was done in a previous model (38), whereas dynamic changes in C5a concentration can be fitted to whole-blood infection experiments inspected with higher temporal resolution. Such a hybrid agentbased model is extensible and resembles the whole-blood infection assay to a high degree of realism allowing for the quantification of the relative impact of complement and morphotype mechanisms.…”

Effects of hemin, CO2, and pH on the branching of Candida albicans filamentous forms

“…It is important to note that hemin is released by oxidized ferric (Fe 3+ ) hemoglobin in the human body [60], and hemin has been demonstrated to initiate the Y → H morphological transition of C. albicans in vitro [13,14], which is likely to facilitate the superficial invasion of the oral mucosa by C. albicans in vivo [50,61,62]. On the other hand, highly branched mycelium can be the prerequisite of an effective nutrient assimilation and may also moderate the invasiveness of C. albicans [45] in the oral cavity as well.…”

Oral candidal carriage and species identification among betel quid chewers and oral submucous fibrosis patients

“…[17][18][19][20] The prevalence of Candida isolates in oral cavity is regulated by endogenous factors such as: (a) Oral epithelial cell antimicrobial peptides such as defensins, cathelicidins and histidine, and epithelial integrity, (b) salivary constituents such as salivary immunoglobulin A, lysozyme, histidine-rich polypeptides, lactoferrin, and lactoperoxidase, and (c) oral cavity temperature and exogenous factors such as high carbohydrate diet. [21][22][23][24] The epithelial cells provide a greater surface area which may promote Candida adhesion.…”