Metabolomic Analysis of Diverse Mice Reveals Hepatic Arginase-1 as Source of Plasma Arginase in Plasmodium chabaudi Infection.

Infections disrupt host metabolism, but the factors that dictate the nature and magnitude of metabolic change are incompletely characterized. To determine how host metabolism changes in relation to disease severity in murine malaria, we performed plasma metabolomics on eight Plasmodium chabaudi-infected mouse strains with diverse disease phenotypes. We identified plasma metabolic biomarkers for both the nature and severity of different malarial pathologies. A subset of metabolic changes, including plasma arginine depletion, match the plasma metabolomes of human malaria patients, suggesting new connections between pathology and metabolism in human malaria. In our malarial mice, liver damage, which releases hepatic arginase-1 (Arg1) into circulation, correlated with plasma arginine depletion. We confirmed that hepatic Arg1 was the primary source of increased plasma arginase activity in our model, which motivates further investigation of liver damage in human malaria patients. More broadly, our approach shows how leveraging phenotypic diversity can identify and validate relationships between metabolism and the pathophysiology of infectious disease. IMPORTANCE Malaria is a severe and sometimes fatal infectious disease endemic to tropical and subtropical regions. Effective vaccines against malaria-causing Plasmodium parasites remain elusive, and malaria treatments often fail to prevent severe disease. Small molecules that target host metabolism have recently emerged as candidates for therapeutics in malaria and other diseases. However, our limited understanding of how metabolites affect pathophysiology limits our ability to develop new metabolite therapies. By providing a rich data set of metabolite-pathology correlations and by validating one of those correlations, our work is an important step toward harnessing metabolism to mitigate disease. Specifically, we showed that liver damage in P. chabaudi-infected mice releases hepatic arginase-1 into circulation, where it may deplete plasma arginine, a candidate malaria therapeutic that mitigates vascular stress. Our data suggest that liver damage may confound efforts to increase levels of arginine in human malaria patients.

Host Energy Source Is Important for Disease Tolerance to Malaria.

Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3-6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7-9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival; treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance.

Infection-related declines in chill coma recovery and negative geotaxis in Drosophila melanogaster.

Studies of infection in Drosophila melanogaster provide insight into both mechanisms of host resistance and tolerance of pathogens. However, research into the pathways involved in these processes has been limited by the relatively few metrics that can be used to measure sickness and health throughout the course of infection. Here we report measurements of infection-related declines in flies' performance on two different behavioral assays. D. melanogaster are slower to recover from a chill-induced coma during infection with either Listeria monocytogenes or Streptococcus pneumoniae. L. monocytogenes infection also impacts flies' performance during a negative geotaxis assay, revealing a decline in their rate of climbing as part of their innate escape response after startle. In addition to providing new measures for assessing health, these assays also suggest pathological consequences of and metabolic shifts that may occur over the course of an infection.