Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence acute lung injury and disease severity are critical. Here, we established the dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, and disease severity using an integrative model-experiment exchange. The model predicts that infection resolution is sensitive to CD8 expansion, that there is a critical T cell magnitude needed for efficient resolution, and that the rate of T cell-mediated clearance is dependent on infected cell density. We used whole lung histomorphometry to validate the model, which showed that the infected area matched the model-predicted infected cell dynamics, and that the resolved area paralleled the relative CD8 dynamics. Additional analysis revealed a nonlinear relation between disease severity (i.e., weight loss) and lung injury. These novel links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.
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