Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection
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eLife assessment
This important study examines the role of TNF in modulating energy metabolism during parasite infection. The authors perform an elegant set of studies, however the evidence supporting the major claims of the manuscript is incomplete. This work integrates an interesting set of observations that will be of interest to the Plasmodium and pathogenesis communities with an expanded set of experiments.
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Abstract
TNF has a dual effect in Plasmodium infection, bolstering the host’s immune defense while also triggering disease. Here, we show that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen as well as controlling parasitemia in P. chabaudi ( Pc )-infected mice. We also demonstrate that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of HIF-1α, expression of glucose transporter GLUT1 and enhanced glycolysis in monocytic cells from Pc -infected mice. Importantly, Pc - infected iNOS -/- , TNFR ΔLyz2 and HIF-1α ΔLyz2 mice show impaired release of TNF and glycolysis in monocytes, together with increased parasitemia and disease tolerance. Together, our findings reveal that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc -infected mice.
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eLife assessment
This important study examines the role of TNF in modulating energy metabolism during parasite infection. The authors perform an elegant set of studies, however the evidence supporting the major claims of the manuscript is incomplete. This work integrates an interesting set of observations that will be of interest to the Plasmodium and pathogenesis communities with an expanded set of experiments.
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Reviewer #1 (Public Review):
Summary:
The manuscript by Kely C. Matteucc et al. titled "Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection" describes that TNF induces HIF-1α stabilization that increases GLUT1 expression as well as glycolytic metabolism in monocytic and splenic CD11b+ cells in P. chabaudi infected mice. Also, TNF signaling plays a crucial role in host energy metabolism, controlling parasitemia, and regulating the clinical symptoms in experimental malaria.
Weaknesses:
Even though iNOS deficiency reduced the expression of the glycolytic enzymes as well as reduced GLUT1 expression and lower ECAR in splenic monocytes, there is no data to support that RNI induces the expression and stabilization of HIF-1α.
This paper involves an incredible …
Reviewer #1 (Public Review):
Summary:
The manuscript by Kely C. Matteucc et al. titled "Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection" describes that TNF induces HIF-1α stabilization that increases GLUT1 expression as well as glycolytic metabolism in monocytic and splenic CD11b+ cells in P. chabaudi infected mice. Also, TNF signaling plays a crucial role in host energy metabolism, controlling parasitemia, and regulating the clinical symptoms in experimental malaria.
Weaknesses:
Even though iNOS deficiency reduced the expression of the glycolytic enzymes as well as reduced GLUT1 expression and lower ECAR in splenic monocytes, there is no data to support that RNI induces the expression and stabilization of HIF-1α.
This paper involves an incredible amount of work, and the authors have done an exciting study addressing the TNF-iNOS-HIF-1α axis as a critical role in host immune defense during Plasmodium infection.
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Reviewer #2 (Public Review):
Summary:
The premise of the manuscript by Matteucci et al. is interesting and elaborates on a mechanism via which TNFa regulates monocyte activation and metabolism to promote murine survival during Plasmodium infection. The authors show that TNF signaling (via an unknown mechanism) induces nitrite synthesis, which (via yet an unknown mechanism), and stabilizes the transcription factor HIF1a. Furthermore, HIF1a (via an unknown mechanism) increases GLUT1 expression and increases glycolysis in monocytes. The authors demonstrate that this metabolic rewiring towards increased glycolysis in a subset of monocytes is necessary for monocyte activation including cytokine secretion, and parasite control.
Strengths:
The authors provide elegant in vivo experiments to characterize metabolic consequences of Plasmodium …
Reviewer #2 (Public Review):
Summary:
The premise of the manuscript by Matteucci et al. is interesting and elaborates on a mechanism via which TNFa regulates monocyte activation and metabolism to promote murine survival during Plasmodium infection. The authors show that TNF signaling (via an unknown mechanism) induces nitrite synthesis, which (via yet an unknown mechanism), and stabilizes the transcription factor HIF1a. Furthermore, HIF1a (via an unknown mechanism) increases GLUT1 expression and increases glycolysis in monocytes. The authors demonstrate that this metabolic rewiring towards increased glycolysis in a subset of monocytes is necessary for monocyte activation including cytokine secretion, and parasite control.
Strengths:
The authors provide elegant in vivo experiments to characterize metabolic consequences of Plasmodium infection, and isolate cell populations whose metabolic state is regulated downstream of TNFa. Furthermore, the authors tie together several interesting observations to propose an interesting model.
Weaknesses:
The main conclusion of this work - that "Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF1a axis plays a key role in host resistance to Plasmodium infection" is unsubstantiated. The authors show that TNFa induces GLUT1 in monocytes, but never show a direct role for GLUT1 or glucose uptake in monocytes in host resistance to infection (nor the hypoglycemia phenotype they describe).
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