A hypometabolic defense strategy against malaria

Ramos, Susana; Ademolue, Temitope W.; Jentho, Elisa; Wu, Qian; Guerra, Joel; Martins, Rui; Pires, Gil; Weis, Sebastian; Carlos, Ana Rita; Mahú, Inês; Rajas, Fabienne; Cardoso, Sílvia; Sousa, António G G; Lilue, Jingtao; Paixão, Tiago; Mithieux, Gilles; Nogueira, Fátima; Soares, Miguel P.

doi:10.1016/j.cmet.2022.06.011

Cited by 17 publications

(14 citation statements)

References 105 publications

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“…Fth deletion in T reg cells increased susceptibility to malaria (Fig. 8E ), consistent with dysregulation of Fe metabolism promoting malaria lethality (Ferreira et al, 2008 ; Ramos et al, 2022 ; Ramos et al, 2019 ; Wu et al, 2023 ). This was associated with an increase in host-parasite burden (Fig.…”

Section: Discussionsupporting

confidence: 57%

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Wu,

Carlos,

Braza

et al. 2024

EMBO J

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Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten–eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

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Section: Discussionsupporting

confidence: 57%

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Wu,

Carlos,

Braza

et al. 2024

EMBO J

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“…For several decades the metabolic relationships between parasites and infected erythrocytes were the focus of intense research leading to a better understanding of parasite biology, identification of anti-malarial drugs, and drug resistance mechanisms ( 21 ). However, it was recently proposed that the host’s systemic and cellular metabolism play a role in the response to infection ( 22 , 23 ). In Plasmodium chabaudi AJ murine non-cerebral malaria model, perturbation of glycolysis using 2-deoxy-D-glucose (2-DG) reduced mice survival while administration of glucose showed protective effects ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism

et al. 2023

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IntroductionCerebral malaria (CM) lethality is attributable to induction of brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored.ResultsActivation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in CM development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing/folding and antigen presentation. In vitro assays showed that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation and Wnt/ß-catenin signaling.DiscussionMetabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and amino acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Together the results show that increase in glucose uptake upon IE exposure licenses Type 1 IFN signaling and subsequent immunoproteasome activation contributing to enhanced antigen presentation and impairment of endothelial barrier function. This work raises the hypothesis that Type 1 IFN signaling-immunoproteasome induction in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells and (2) by promoting endothelial barrier dysfunction, that likely favor brain vasogenic edema.

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“…13 Current mouse models support a downregulation of hepatic glucose associated with heme release after erythrocyte apoptosis. 14 Similarly, the degree of clinical benefit of glucose administration to children with hypoglycemia or to those with blood glucose values between 2.2 mmol/L and 3.0 mmol/L is also unknown. Because administration of glucose in those with hypoglycemia is not thought to be harmful, a clinical trial to determine the degree of benefit of glucose supplementation in children with hypoglycemia is likely unethical.…”

Section: Discussionmentioning

confidence: 99%

Temporal Trends of Blood Glucose in Children with Cerebral Malaria

Chastang

Imam

Sherman

et al. 2023

The American Journal of Tropical Medicine and Hygiene

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Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35–6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51–6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85–8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

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A hypometabolic defense strategy against malaria

Cited by 17 publications

References 105 publications

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism

Temporal Trends of Blood Glucose in Children with Cerebral Malaria

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