title: Mathematical Modeling ofStreptococcus pneumoniaeColonization, Invasive Infection and Treatment.
abstract: Streptococcus pneumoniae(Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenza virus can impair the complexSp-host interactions and the subsequent development of many life-threatening infectious and inflammatory diseases, including pneumonia, meningitis or even sepsis. With the increased threat ofSpinfection due to the emergence of new antibiotic resistantSpstrains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered bySpinfection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms ofSp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understanding of the complex and dynamically-changing host-Spinteractions, here we developed a mechanistic mathematical model describing dynamic interplays betweenSp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains variousin vitroandin vitrostudies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostaticSp-host interaction, as well as three qualitatively different pathogenic behaviors: immunological scarring, invasive infection and their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathological behaviors. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transientSpchallenges. This prediction provides arguments in favor of the use of vaccinations, since adaptive immune responses cannot be developedde novoin such a short time. We further designed optimal treatment strategies, with minimal strengths and minimal durations of antibiotics, for each of the three pathogenic behaviors distinguished by our model. The proposed mathematical framework will help to design better disease management strategies and new diagnostic markers that can be used to inform the most appropriate patient-specific treatment options.
authors.affiliation: Department of Bioengineering, Imperial College LondonLondon, UK; Instituto de Ecología, Universidad Nacional Autónoma de MéxicoMexico City, Mexico.
authors.forename: Elisa
authors.initials: E
authors.lastname: Domínguez-Hüttinger
authors.affiliation: Department of Bioengineering, Imperial College London London, UK.
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Boon
authors.affiliation: Department of Medicine, Imperial College London London, UK.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarke
authors.affiliation: Department of Bioengineering, Imperial College London London, UK.
authors.forename: Reiko J
authors.initials: RJ
authors.lastname: Tanaka
keywords: Streptococcus pneumoniae; antibiotics resistance; commensal bacteria; data integration; hybrid systems; systems biology; upper airway epithelium