Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling

Gardinassi, Luiz Gustavo; Arévalo‐Herrera, Myriam; Herrera, Sócrates; Cordy, Regina Joice; Tran, ViLinh; Smith, M. R.; Johnson, Michelle S.; Chacko, Balu K.; Liu, Ken H.; Darley‐Usmar, Victor; Go, Young‐Mi; Jones, Dean P.; Galinski, Mary R.; Li, Shuzhao

doi:10.1016/j.redox.2018.04.011

Cited by 63 publications

(52 citation statements)

References 67 publications

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“…Our results corroborate the increase in KYN/TRP ratio in naturally acquired P vivax malaria, as demonstrated in human‐controlled P vivax infections . Also, our observations are consistent with recent studies that characterized serum metabolomics of Plasmodium ‐infected humans and nonhuman primates . IFN‐γ was shown to be essential for IDO1 induction, and mice genetically deficient for IDO1 were not protected against cerebral malaria in a P berghei ANKA (PbA) mouse model.…”

Section: Discussionsupporting

confidence: 91%

“…18 Also, our observations are consistent with recent studies that characterized serum metabolomics of Plasmodium-infected humans and nonhuman primates. [30][31][32] IFN-γ was shown to be essential for IDO1 induction, 33 and mice genetically deficient for IDO1 were not protected against cerebral malaria 34 The increase of Tregs has been demonstrated in acute human and murine malaria infections. [12][13][14]36,37 Previously in P falciparum infections, it was demonstrated that IL-10 and Tregs cells frequencies are influenced by malaria incidence and by the number of malaria infections.…”

Section: Discussionmentioning

confidence: 99%

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Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

Santos¹,

Gonçalves-Lopes

Lima

et al. 2020

Parasite Immunology

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Background Disease‐tolerance mechanisms limit infection severity by preventing tissue damage; however, the underlying mechanisms in human malaria are still unclear. Tryptophan (TRP), an essential amino acid, is catabolized into tolerogenic metabolites, kynurenines (KYN), by indoleamine 2,3‐dioxygenase 1 (IDO1), which can induce Foxp3+ T regulatory cells (Tregs). In this study, we evaluated the relationship of these metabolites with Treg‐mediated tolerance induction in acute malaria infections. Methods We performed a cross‐sectional study that evaluated asymptomatic, symptomatic malaria patients and endemic control patient groups. We assessed plasmatic concentration of cytokines by ELISA. Plasmatic TRP and KYN levels were measured by HPLC. Peripheral T regulatory cells were measured and phenotyped by flow cytometry. Results The KYN/TRP ratio was significantly elevated in asymptomatic and symptomatic Plasmodium infection, compared to healthy controls. Also, Th1 and Th2 cytokines were elevated in the acute phase of malaria disease. IFN‐γ increase in acute phase was positively correlated with the KYN/TRP ratio and KYN elevation was positively correlated with the increase of peripheral FoxP3+ T regulatory cells. Conclusions Additional studies are needed not only to identify innate mechanisms that increase tryptophan catabolism but also the role of Tregs in controlling malaria‐induced pathology and malaria tolerance by the host.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

Santos¹,

Gonçalves-Lopes

Lima

et al. 2020

Parasite Immunology

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“…Studies from P. vivax- infected patients also reveal that parasitemia is significantly associated with metabolites involved in lipid metabolism, an observation that may be tied to their intracellular growth ( Gardinassi et al, 2017 ). Conversely, in a study observing factors associated with pre-existing P. vivax immunity, semi-immune subjects exhibit increased levels of linoleate metabolites compared to naive subjects ( Gardinassi et al, 2018 ). The ability of an infected individual to respond to malaria treatment may also be tied to host lipids, where patients with lower levels of baseline glycerophosphocholines were more likely to develop chloroquine-resistant malaria after infection ( Uppal et al, 2017 ).…”

Section: Immune Evasion and Disease Severitymentioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

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Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasite Plasmodium falciparum and the Lyme disease spirochete Borrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In this Review, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

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“…previous exposure (Gardinassi et al, 2018;Cordy et al, 2019). We recently observed that acute Plasmodium infection induced an IFN-γ-driven increment in serum kynurenines that correlated with an elevation in the frequency of circulating FoxP3 + T regulatory cells in a hypo-endemic Amazon region (Dos Santos et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

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

Santos¹,

Cruz²,

Lopes³

et al. 2020

Front. Microbiol.

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The human immune response that controls Plasmodium infection in the liver and blood stages of the parasite life cycle is composed by both pro-and anti-inflammatory programs. Pro-inflammatory responses primarily mediated by IFN-γ controls the infection, but also induce tolerogenic mechanisms to limit host damage, including the tryptophan (TRP) catabolism pathway mediated by the enzyme Indoleamine 2,3-Dioxygenase (IDO1), an enzyme that catalyzes the degradation of TRP to kynurenines (KYN). Here we assessed total serum kynurenines and cytokine dynamics in a cohort of natural Plasmodium vivax human infection and compared them to those of endemic healthy controls and other febrile diseases. In acute malaria, the absolute free kynurenine (KYN) serum levels and the KYN to TRP (KYN/TRP) ratio were significantly elevated in patients compared to healthy controls. Individuals with a diagnosis of a first malaria episode had higher serum KYN levels than individuals with a previous malaria episode. We observed an inverse relationship between the serum levels of IFN-γ and IL-10 in patients with a first malaria episode compared to those of subjects with previous history of malaria. Kynurenine elevation was positively correlated with serum IFN-γ levels in acute infection, whereas, it was negatively correlated with parasite load and P. vivax LDH levels. Overall, the differences observed between infected individuals depended on the number of Plasmodium infections. The decrease in the KYN/TRP ratio in malariaexperienced subjects coincided with the onset of anti-P. vivax IgG. These results suggest that P. vivax infection induces a strong anti-inflammatory program in individuals with first time malaria, which fades with ensuing protective immunity after subsequent episodes. Understanding the tolerance mechanisms involved in the initial exposure would help in defining the balance between protective and pathogenic immune responses necessary to control infection and to improve vaccination strategies.

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Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling

Cited by 63 publications

References 67 publications

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

Lipid hijacking: A unifying theme in vector-borne diseases

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

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