Influenza A virus (IAV) infection enhances host susceptibility to bacterial pathogens such as Streptococcus pneumoniae, resulting in severe respiratory diseases, high rates of hospitalization and death. Although several aspects of the lethal synergism between IAV / S. pneumoniae coinfections have been explored, a holistic understanding of the synergistic action of viral and bacterial pathogens that is key to the design of effective therapeutic interventions, remains elusive to date. To fill existing knowledge gaps the collaborative research project proposed here will utilize an interdisciplinary approach intertwining mathematical modeling, engineering approaches, and tailored in vivo mouse infection experiments. The major objectives of this project are i) to develop within-host mathematical models to quantify the host regulatory mechanisms being active during IAV infections and to predict and possibly prevent the complications of a severe secondary bacterial infection ii) to create and implement innovative nonlinear observers as an in silico tool to provide better prognosis of infections iii) to clarify the role of interferon-γ released following virus encounter by natural killer cells and CD8+ T cells in impaired alveolar macrophage functions as a potential underlying mechanism for enhanced susceptibility to bacterial coinfection following influenza. The proposed iterative process in which models and engineering tools will be progressively refined based on individually fitted infection experiments, will enable the formulation of more valid hypotheses. Ultimately, we are aiming towards a complete understanding of the processes underlying the synergism between IAV and S. pneumoniae which will be the crucial basis for the development of strategies for treatment and prophylaxis in the future.