Host-pathogen interactions between the human innate immune system and Candida albicans-understanding and modeling defense and evasion strategies

Abstract

The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.

Keywords: Candida albicans; computational systems biology; defense and evasion strategies; host-pathogen interaction; human immune system; immunological cross-talk.

Figure 1

Depiction of oxidative and nitrosative stress imposed on phagocytosed C. albicans and its detoxification by the fungus. The Curved lines indicate cell membranes of the phagocyte, the phagolysosome and, most inside, the C. albicans cell. Abbreviations: iNOS, inducible nitric oxide synthase; Cta1, catalase 1; Sod1-6, superoxide dismutases 1–6; Gpxs, glutathione peroxidases; GRX2 and GRL1 encode glutathione reductases; Yhb1, Yhb4, and Yhb5, flavohemoglobin 1, 4, and 5; Hog1, mitogen-activated protein kinase; Cap1, adenylate cyclase-associated protein; Cta4, transcription factor; Cwt1, cell wall transcription factor.

Figure 2

Screenshot of a typical ABM simulation (taken from Tokarski et al., 2012), displaying the hunt of free-moving neutrophil agents (black circles) for immobile spore agents of Aspergillus fumigatus in human lung tissue. Spores can be free (orange), temporarily dragged (yellow) or caught (red) by a neutrophil agent. Dragged spores may be released with a certain probability or caught and phagocytosed (gray). Neutrophil agents are able to detect chemokines (blue), released by spores during sporulation, and may adjust their movement accordingly.