Modeling Candida albicans complex-mediated evasion and in silico treatment strategies: a systems biology approach

Understanding host-pathogen interactions is critical for developing effective treatments in the context of infections. The human-pathogenic fungus Candida albicans employs sophisticated mechanisms to evade human immune defenses. Previously, we investigated and modeled one of the key immune evasion strategies used by C. albicans to defend itself against antimicrobial peptides (AMP), termed complex-mediated evasion (CME) [1]. According to this mechanism, C. albicans secretes the Msb2* protein into the extracellular space, which binds to human AMP such as LL-37, thereby preventing their antimicrobial action and enhancing the pathogen’s survival. Following a systems biology approach, we now combine experimental and computational methods to deepen the mechanistic understanding of CME and identify potential therapeutic interventions. Guided by sensitivity analyses from our previous model based on partial differential equations (PDE) [1], we conducted survival assays and live-cell imaging experiments to refine and accurately estimate model parameters using the same computationally efficient PDE model. Subsequently, we implemented an agent-based model (ABM), which accounts for the molecular crowding of the environment, to perform more accurate and detailed simulations of CME. To overcome the computationally intensive stochastic simulations of the ABM, we used parameters derived from the PDE model to limit the parameter space, enabling in silico testing of targeted treatments aimed at neutralizing Msb2*. Simulation results demonstrated that drugs specifically designed to bind to Msb2* effectively restored the susceptibility of C. albicans to LL-37-mediated killing. Collectively, our integrative systems biology approach highlights the potential for targeted therapies against virulence factors such as Msb2* to counteract pathogen immune evasion strategies. [1] Y. Bachelot, A. Solomatina, and M. T. Figge, “Complex-mediated evasion: modeling defense against antimicrobial peptides with application to human-pathogenic fungus Candida albicans”, doi: 10.1038/s41540-025-00559-1.