Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Gordon, Emile B.; Hart, Geoffrey T.; Tran, Tuan M.; Waisberg, Michael; Akkaya, Munir; Kim, Ann S.; Hamilton, Sara E.; Peña, Mirna; Yazew, Takele; Chen, Qi; Lee, Chen Fang; Lo, Ying Chun; Miller, Louis H.; Powell, Jonathan D.; Pierce, Susan K.

doi:10.1073/pnas.1516544112

Cited by 72 publications

(79 citation statements)

References 37 publications

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“…5A). In contrast, as described recently (Gordon et al, 2015), the GAP50 40–48 -specific naive repertoire was extraordinarily large (2,935 ± 305 cells, Fig. 5A).…”

Section: Resultssupporting

confidence: 68%

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

et al. 2017

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SUMMARY Immune response (Ir) genes, originally proposed by Baruj Benacerraf to explain differential antigen-specific responses in animal models, have become synonymous with the major histocompatibility complex (MHC). We discovered a non-MHC-linked Ir gene in a T cell receptor (TCR) locus that was required for CD8+ T cell responses to the Plasmodium berghei GAP5040–48 epitope in mice expressing the MHC class I allele H-2Db. GAP5040–48-specific CD8+ T cell responses emerged from a very large pool of naive Vβ8.1+ precursors, which dictated susceptibility to cerebral malaria and conferred protection against recombinant Listeria monocytogenes infection. Structural analysis of a prototypical Vβ8.1+ TCR-H-2Db-GAP5040–48 ternary complex revealed that germline-encoded complementarity-determining region 1β residues present exclusively in the Vβ8.1 segment mediated essential interactions with the GAP5040–48 peptide. Collectively, these findings demonstrated that Vβ8.1 functioned as an Ir gene that was indispensable for immune reactivity against the malaria GAP5040–48 epitope.

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“…5A). In contrast, as described recently (Gordon et al, 2015), the GAP50 40–48 -specific naive repertoire was extraordinarily large (2,935 ± 305 cells, Fig. 5A).…”

Section: Resultssupporting

confidence: 68%

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

et al. 2017

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“…The definition of severe disease used in the current study was based on the fact that cerebral malaria is exceedingly rare in the region (83). This distinction may be important in the context of recent findings in murine experimental cerebral malaria, in which administration late in the infection of a glutamine analog, 6-diazo-5-oxo-L-norleucine, which broadly inhibits Gln metabolism, rescues mice from the manifestations of severe disease, including blood-brain barrier dysfunction, brain swelling and hemorrhaging, and accumulation of parasite-specific CD8 + effector T cells and infected red blood cells in the brain (84). It remains to be determined if Gln supplementation as an adjunctive treatment in the context of antimalarial chemotherapy provides differing clinical outcomes in children with cerebral malaria versus those with SMA.…”

Section: Discussionmentioning

confidence: 99%

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Kempaiah

Dokładny

Karim

et al. 2016

Mol Med

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Severe malarial anemia (SMA; hemoglobin [Hb] <5.0 g/dL) is a leading global cause of morbidity and mortality among children residing in Plasmodium falciparum transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased HSPA1A, a heat shock protein 70 (Hsp70) coding gene. Hsp70 is a ubiquitous chaperone that regulates nuclear factor-kappa B (NF-κB) signaling and production of proinflammatory cytokines known to be important in malaria pathogenesis (for example, IL-1β, IL-6 and TNF-α). Since the role of host Hsp70 in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocytic HSP70 transcripts were reduced in SMA relative to nonsevere malaria, and that intraleukocytic hemozoin (PfHz) was associated with lower HSP70. HSP70 was correlated with reticulocyte production and Hb. Since glutamine (Gln) upregulates Hsp70, modulates NF-κB activation and attenuates overexpression of proinflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA. Treatment of cultured peripheral blood mononuclear cells (PBMCs) with PfHz caused a time-dependent decrease in Hsp70 transcripts/protein and NF-κB activation. Gln treatment of PBMCs overcame PfHz-induced suppression of HSP70 transcripts/protein, reduced NF-κB activation and suppressed overexpression of IL-1β, IL-6 and TNF-α. These findings demonstrate that SMA is characterized by reduced intraleukocytic HSP70 and circulating Gln, and that PfHz-induced suppression of HSP70 can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.

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“…In models of allograft skin and heart transplantation, the metabolic therapy markedly promoted allograft acceptance. In addition, inhibiting glutamine metabolism with DON has been shown to effectively inhibit severe inflammation and to promote survival in mouse models of cerebral malaria and viral encephalitis [25,26]. …”

Section: Targeting T Cells Through Amino Acidsmentioning

confidence: 99%

Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease

Patel

Powell

2017

Current Opinion in Immunology

100

107

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Summary It is becoming increasingly clear that metabolic reprogramming plays a critical role in T cell activation, differentiation and function. To this end, cellular metabolism not only meets the energetic demands of T cells but also provides critical substrates for their growth and function. Furthermore, metabolites themselves are emerging as key regulators of immune responses. As the details of how metabolic reprogramming regulates immune function are revealed, new potential targets for modulating immune responses have emerged. Indeed, the distinct metabolic demands of different T cell subsets make them exquisitely sensitive to pharmacologic inhibitors of metabolism. In this review, we will describe the emerging strategies whereby targeting metabolism can shape the T cell response.

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Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Cited by 72 publications

References 37 publications

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease

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