Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

Myers, Margaret A; Smith, Amanda P; Lane, Lindey C; Moquin, David J; Aogo, Rosemary; Woolard, Stacie; Thomas, Paul; Vogel, Peter; Smith, Amber M

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8(+) T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8(+) T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8(+) T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8(+) T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8(+) T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.