Glucose metabolism mediates disease tolerance in cerebral malaria

Abstract

Sickness behaviors are a conserved set of stereotypic responses to inflammatory diseases. We recently demonstrated that interfering with inflammation-induced anorexia led to metabolic changes that had profound effects on survival of acute inflammatory conditions. We found that different inflammatory states needed to be coordinated with corresponding metabolic programs to actuate tissueprotective mechanisms. Survival of viral inflammation required intact glucose utilization pathways, whereas survival of bacterial inflammation required alternative fuel substrates and ketogenic programs. We thus hypothesized that organismal metabolism would be important in other classes of infectious inflammation and sought to understand its role in the prototypic parasitic disease malaria. Utilizing the cerebral malaria model, Plasmodium berghei ANKA (PbA) infection in C57BL/6J male mice, we unexpectedly found that inhibition of glycolysis using 2-deoxy glucose (2DG) conferred protection from cerebral malaria. Unlike vehicletreated animals, 2DG-treated animals did not develop cerebral malaria and survived until ultimately succumbing to fatal anemia. We did not find any differences in parasitemia or pathogen load in affected tissues. There were no differences in the kinetics of anemia. We also did not detect differences in immune infiltration in the brain or in blood-brain barrier permeability. Rather, on pathological analyses performed on the entire brain, we found that 2DG prevented the formation of thrombi and thrombotic complications. Using thromboelastography (TEG), we found that 2DGtreated animals formed clots that were significantly less strong and stable. Together, these data suggest that glucose metabolism is involved in inflammation-induced hemostasis and provide a potential therapeutic target in treatment of cerebral malaria. malaria | inflammation | metabolism

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.…”

A First Plasmodium vivax Natural Infection Induces Increased Activity of the Interferon Gamma-Driven Tryptophan Catabolism Pathway

“…Our understanding of how, in the context of moderate to high exposure to parasite and host components in the bloodstream of malaria-infected subjects, the majority of clinical cases lack overt clinical disease and complications is still limited (Sinton, 1938;Crompton et al, 2014). In addition to evolutionary human adaptation to malaria parasites that confer host resistance (Júnior et al, 2010;Piel et al, 2013;Vale, 2018;Wang et al, 2018), multiple mechanisms have been proposed to explain malaria tolerance. In this study, we observed that IFN-γ and serum kynurenines increase to both control the infection and to avoid host immunopathology.…”

Glucose-mediated expansion of a gut commensal bacterium promotesPlasmodiuminfection through alkalizing mosquito midgut

“…Plasmodium parasites have lost multiple genes involved in nutrient synthesis and have to compete with their hosts for essential nutrients (Gardner et al, 2002). Both liver and blood stage malaria parasites scavenge host glucose for their energetic needs (Meireles et al, 2016;Olszewski and Llinas, 2011;Stanway et al, 2019;Wang et al, 2018). However, little is known about the crosstalk between glucose metabolism of Anopheles and that of Plasmodium.…”