A combined modeling framework to break the lethal alliance between influenza and bacterial coinfections

甲型流感病毒（IAV）感染增强了宿主对肺炎链球菌等细菌病原体的易感性，导致严重的呼吸道疾病、高住院率和高死亡率。虽然已经探索了IAV /肺炎链球菌共感染之间致命协同作用的几个方面，但对病毒和细菌病原体的协同作用的整体理解是设计有效治疗干预措施的关键，迄今为止仍然难以捉摸。为了填补现有的知识空白，这里提出的合作研究项目将利用跨学科的方法，将数学建模、工程方法和量身定制的小鼠体内感染实验相结合。该项目的主要目标是：1)建立宿主内部数学模型，以量化在IAV感染期间活跃的宿主调节机制，并预测和可能预防严重继发性细菌感染的并发症；2)创建和实施创新的非线性观察者，作为一种计算机工具，提供更好的感染预后；3)阐明干扰素γ在自然杀伤细胞和CD8+ T细胞遇到病毒后释放的作用肺泡巨噬细胞功能受损可能是流感后细菌合并感染易感性增强的潜在机制。提出的迭代过程中，模型和工程工具将根据单独拟合的感染实验逐步完善，这将使制定更有效的假设成为可能。最终，我们的目标是全面了解IAV和肺炎链球菌之间协同作用的过程，这将是未来制定治疗和预防策略的关键基础。

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.