Patients with severe malaria can experience parasitemia levels exceeding 10%, while also suffering from symptoms such as fever, anemia and renal impairment. The symptoms can be attributed to the disease as well as the immune response to disease. Indicative of a poor prognosis, some patients also present with hyperlactatemia and hypoglycemia, attributed to changes to the host metabolism during infection as well as an increase in glycolytic flux through the parasite.

To investigate the effects of disease and parasite metabolism on disease manifestation and metabolic abnormalities a multi-scale model was developed. The model linked two existing models: 1) a within-host disease model that incorporates the immune response and, 2) a whole-body glucose metabolism model that includes parasite metabolism. The models were linked in two steps. The top-down linking of the models used comparable variables and mapped the red blood cell (RBC) populations from the disease model to the metabolic model. The bottom-up linking mapped the parasite ATP production rate to biomass formation in the disease model. A Monte-Carlo simulation was performed and model predictions were compared to clinical data from literature.

Sensitivity analysis on the linked model suggested that processes that affect the disease and immune response have the largest effects on parasitemia and hematocrit, while parasite glycolysis and the total number of RBCs have the largest effects on blood lactate and glucose levels. Additionally, the model also suggested that the innate immune response, and more specifically innate immune cell longevity, has a greater effect on disease outcome than the adaptive immune response.

Seven treatments were added to the model targeting specific processes. Two treatments affect the disease directly by blocking the invasion of healthy RBCs and by reducing the number of merozoites released per bursting iRBC. Two treatments enhance the innate immune response, one by increasing its efficiency and one by increasing its production. The last three treatments all targeted parasite glycolysis by inhibiting the glucose transporter, hexokinase or phosphofructokinase.

Comparison of the treatment effects indicated that targeting the proliferation of merozoites within the infected RBC is most efficient, while glycolytic inhibitors, although less effective against disease itself, led to the best treatment of hyperlactatemia and hypoglycemia.