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Influenza virus infections are often complicated by coinfection with bacterial pathogens, such as pneumococcus. These bacterial coinfections significantly increase influenza-associated morbidity and mortality. The host immune response plays a large role in driving bacterial establishment and the progression to pneumonia. However, it is not well understood how the host response is regulated and how it works to modulate pathogen growth. To better characterize the regulatory mechanisms driving influenza-pneumococcal coinfection, we use an integrative analysis that combines data-driven mathematical models with model-driven experiments. Through this iterative model-data approach, we identified and detailed the nonlinear way in which virus-induced depletion of alveolar macrophages regulates bacterial invasion and can lead to differential dynamics dependent on the time of bacterial acquisition.ÌýWe then utilize this relationÌýto evaluate potential treatment strategies. These results provide insight into the probability of acquiring a coinfection,Ìýthe heterogeneity in outcome, and the use of new therapies that prevent viral-bacterial coinfections.Ìý