Host Energy Source Is Important for Disease Tolerance to Malaria

Abstract

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.

Glucose metabolism mediates disease tolerance in cerebral malaria

“…2). These findings are consistent with recent studies utilizing the P. chabaudi AJ model, where 2DG was likely exacerbating the damaging effects of severe anemia (25). We thus asked if the addition of the antimalarial antibiotherapy chloroquine would be sufficient to provide long-term survival (Fig.…”

“…In our experiments, 2DG was sufficient to rescue mice from cerebral malaria, but they ultimately succumbed to fatal anemia in the absence of pathogen clearance. Our findings are consistent with those of Cumnock et al (25), who showed that 2DG may be detrimental in severe anemia. Indeed, we were able to rescue 2DG-treated animals that survived cerebral malaria by subsequent treatment with chloroquine, suggesting that any therapeutic use of 2DG for treating cerebral malaria will need to be combined with chemotherapeutic drugs targeting the parasite and that the use of 2DG must be carefully timed to the stage of the disease.…”

“…Ferreira et al (24) recently showed that sickle cell trait did not affect parasite burden but, instead, decreased the amount of circulating free heme and blunting CD8 + T cell responses to the parasite, thereby suppressing pathogenesis of cerebral malaria. Cumnock et al (25) recently demonstrated that survival in the Plasmodium chabaudi AJ model, where mice do not develop cerebral malaria but, instead, fatal anemia, was dependent on glucose metabolism, presumably because severe anemia reduced tissue oxygenation, thereby increasing the demand on processes that required glucose. They demonstrated that the dependence on glucose for mortality in this model was also altering disease tolerance since no changes in pathogen burden were observed.…”

Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

“…We have previously shown that while administration of 2-DG to animals challenged with Poly I:C or influenza resulted in driving the unfolded protein response toward neuronal cell death leading to enhanced mortality, administration of 2-DG to animals challenged with LPS or Listeria resulted in enhanced survival by mechanisms which are yet to be fully identified but independent of the magnitude of the inflammatory response (12). We have also recently shown using mouse models of malaria that 2-DG protected animals from cerebral malaria by affecting hemostasis while others have shown that it potentiates mortality in malarial models of fatal anemia (57,58). It is likely that the composite outcome of 2-DG depends on the given set of biological processes that require glucose in any particular organismal state.…”

Disease Tolerance: Linking Sickness Behaviours to Metabolism Helps Mitigate Malaria

“…In a new study in this issue of Current Biology, Cumnock et al [6] find that mice infected with malaria experience a range of sickness behaviours including anorexia, lethargy and hypothermia. By explicitly testing the link between behavioural and metabolic outputs during the entire infection cycle, the authors showed that these symptoms could be relieved with a relatively simple and cheap treatment that improves glycolysis in severely anaemic mice, making them more tolerant to malaria.…”