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Quantitative Simulations Predict Treatment Strategies Against Fungal Infections in Virtual Neutropenic Patients
Sandra Timme1,2, Teresa Lehnert1,3, Maria T E Prauße1,2
1Research Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
Abstract:
The condition of neutropenia, i.e., a reduced absolute neutrophil count in blood, constitutes a major risk factor for severe infections in the affected patients. Candida albicans and Candida glabrata are opportunistic pathogens and the most prevalent fungal species in the human microbiota. In immunocompromised patients, they can become pathogenic and cause infections with high mortality rates. In this study, we use a previously established approach that combines experiments and computational models to investigate the innate immune response during blood stream infections with the two fungal pathogens C. albicans and C. glabrata. First, we determine immune-reaction rates and migration parameters under healthy conditions. Based on these findings, we simulate virtual patients and investigate the impact of neutropenic conditions on the infection outcome with the respective pathogen. Furthermore, we perform in silico treatments of these virtual patients by simulating a medical treatment that enhances neutrophil activity in terms of phagocytosis and migration. We quantify the infection outcome by comparing the response to the two fungal pathogens relative to non-neutropenic individuals. The analysis reveals that these fungal infections in neutropenic patients can be successfully cleared by cytokine treatment of the remaining neutrophils; and that this treatment is more effective for C. glabrata than for C. albicans.
Insights
Neutropenia increases infection risk from Candida fungi. Cytokine treatment of remaining neutrophils effectively clears these fungal infections, with better results for Candida glabrata than Candida albicans.
Area of Science:
- Immunology
- Computational Biology
- Mycology
Background:
- Neutropenia, a low neutrophil count, elevates the risk of severe infections.
- Candida albicans and Candida glabrata are opportunistic fungal pathogens causing high mortality in immunocompromised individuals.
- Understanding innate immune responses to these fungi is critical for managing infections.
Purpose of the Study:
- To investigate innate immune responses during bloodstream infections with Candida albicans and Candida glabrata.
- To model the impact of neutropenia on infection outcomes.
- To evaluate the efficacy of simulated neutrophil-enhancing cytokine treatment.
Main Methods:
- Combined experimental data with computational modeling.
- Determined immune reaction rates and migration parameters under healthy conditions.
- Simulated virtual patients with neutropenia and assessed infection outcomes.
- Performed in silico treatment simulations to enhance neutrophil activity.
Main Results:
- Neutropenic conditions significantly impact infection outcomes for both Candida species.
- Simulated cytokine treatment successfully cleared fungal infections in neutropenic virtual patients.
- Treatment efficacy was greater against Candida glabrata compared to Candida albicans.
Conclusions:
- Cytokine therapy targeting remaining neutrophils is a viable strategy for treating fungal infections in neutropenic patients.
- The effectiveness of this treatment strategy varies between Candida albicans and Candida glabrata.
- Computational modeling provides valuable insights into host-pathogen dynamics and treatment efficacy.
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