A data-driven model of the role of energy in sepsis.

Exposure to pathogens elicits a complex immune response involving multiple interdependent pathways. This response may mitigate detrimental effects and restore health but, if imbalanced, can lead to negative outcomes including sepsis. This complexity and need for balance pose a challenge for clinicians and have attracted attention from modelers seeking to apply computational tools to guide therapeutic approaches. In this work, we address a shortcoming of such past efforts by incorporating the dynamics of energy production and consumption into a computational model of the acute immune response. With this addition, we performed fits of model dynamics to data obtained from non-human primates exposed to Escherichia coli. Our analysis identifies parameters that may be crucial in determining survival outcomes and also highlights energy-related factors that modulate the immune response across baseline and altered glucose conditions.

Mathematical modeling of energy consumption in the acute inflammatory response.

When a pathogen invades the body, an acute inflammatory response is activated to eliminate the intruder. In some patients, runaway activation of the immune system may lead to collateral tissue damage and, in the extreme, organ failure and death. Experimental studies have found an association between severe infections and depletion in levels of adenosine triphosphate (ATP), increase in nitric oxide production, and accumulation of lactate, suggesting that tissue energetics is compromised. In this work we present a differential equations model that incorporates the dynamics of ATP, nitric oxide, and lactate accompanying an acute inflammatory response and employ this model to explore their roles in shaping this response. The bifurcation diagram of the model system with respect to the pathogen growth rate reveals three equilibrium states characterizing the health, aseptic and septic conditions. We explore the domains of attraction of these states to inform the instantiation of heterogeneous virtual patient populations utilized in a survival analysis. We then apply the model to study alterations in the inflammatory response and survival outcomes in metabolically altered conditions such as hypoglycemia, hyperglycemia, and hypoxia.

Increased virus dissemination leads to enhanced lung injury but not inflammation during influenza-associated secondary bacterial infection.

Secondary bacterial infections increase influenza-related morbidity and mortality, particularly if acquired after 5-7 d from the viral onset. Synergistic host responses and direct pathogen-pathogen interactions are thought to lead to a state of hyperinflammation, but the kinetics of the lung pathology have not yet been detailed, and identifying the contribution of different mechanisms to disease is difficult because these may change over time. To address this gap, we examined host-pathogen and lung pathology dynamics following a secondary bacterial infection initiated at different time points after influenza within a murine model. We then used a mathematical approach to quantify the increased virus dissemination in the lung, coinfection time-dependent bacterial kinetics, and virus-mediated and postbacterial depletion of alveolar macrophages. The data showed that viral loads increase regardless of coinfection timing, which our mathematical model predicted and histomorphometry data confirmed was due to a robust increase in the number of infected cells. Bacterial loads were dependent on the time of coinfection and corresponded to the level of IAV-induced alveolar macrophage depletion. Our mathematical model suggested that the additional depletion of these cells following the bacterial invasion was mediated primarily by the virus. Contrary to current belief, inflammation was not enhanced and did not correlate with neutrophilia. The enhanced disease severity was correlated to inflammation, but this was due to a nonlinearity in this correlation. This study highlights the importance of dissecting nonlinearities during complex infections and demonstrated the increased dissemination of virus within the lung during bacterial coinfection and simultaneous modulation of immune responses during influenza-associated bacterial pneumonia.