Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

Cordy, Regina Joice; Patrapuvich, Rapatbhorn; Lili, Loukia N.; Cabrera-Mora, Mónica; Chien, Jung-Ting; Tharp, Gregory K.; Khadka, Manoj; Meyer, Esmeralda; Lapp, Stacey A.; Joyner, Chester J.; García, Anapatricia; Banton, Sophia; Tran, ViLinh; Luvira, Viravarn; Rungin, Siriwan; Saeseu, Teerawat; Rachaphaew, Nattawan; Pakala, Suman B.; DeBarry, Jeremy D.; Kissinger, Jessica C.; Ortlund, Eric A.; Bosinger, Steven E.; Barnwell, John W.; Jones, Dean P.; Uppal, Karan; Li, Shuzhao; Sattabongkot, Jetsumon; Moreno, Alberto; Galinski, Mary R.

doi:10.1172/jci.insight.125156

Cited by 43 publications

(76 citation statements)

References 78 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 have been done to investigate the metabolic needs of asexually replicating Plasmodium parasites in vitro (Olszewski et al, 2009). Additional studies have focused on metabolites in human blood that are altered during malaria infections (Basant et al, 2010;Pappa et al, 2015;Surowiec et al, 2015;Decuypere et al, 2016;Gardinassi et al, 2017;Uppal et al, 2017;Ghosh et al, 2018;Cordy et al, 2019). This body of work has demonstrated the utility of this tool for identifying a wide range of physiological changes that occur in vertebrate hosts during malaria infection.…”

Section: Metabolites Involved In Gametocyte Developmentmentioning

confidence: 99%

Mining the Human Host Metabolome Toward an Improved Understanding of Malaria Transmission

Cordy

2020

Front. Microbiol.

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The big data movement has led to major advances in our ability to assess vast and complex datasets related to the host and parasite during malaria infection. While host and parasite genomics and transcriptomics are often the focus of many computational efforts in malaria research, metabolomics represents another big data type that has great promise for aiding our understanding of complex host-parasite interactions that lead to the transmission of malaria. Recent analyses of the complement of metabolites present in human blood, skin and breath suggest that host metabolites play a critical role in the transmission cycle of malaria. Volatile compounds released through breath and skin serve as attractants to mosquitoes, with malaria-infected hosts appearing to have unique profiles that further increase host attractiveness. Inside the host, fluctuations in the levels of certain metabolites in blood may trigger increased production of transmission-competent sexual stages (gametocytes), setting the stage for enhanced transmission of malaria from human to mosquito. Together, these recent discoveries suggest that metabolites of human blood, skin and breath play critical roles in malaria transmission. This review discusses recent advances in this area, with a focus on metabolites that have been identified to play a role in malaria transmission and methods that may lead to an improved understanding of malaria transmission.

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“…Our exploratory results grant a more detailed prospective analysis of the relationship between innate immunity, parasitemia, and the balance of pro and anti-inflammatory pathways in human malaria and its dynamics during multiple episodic infections. Of note, we also observed that the tryptophan degradation pathway activity was increased in non-malaria disease as well, suggesting that this pathway is activated by broad non-specific host responses to acute inflammation (Cordy et al, 2019). Previous studies that evaluated the role of the tryptophan degradation pathway in malaria have consistently shown that the activity of IDO1 is deleterious, and that it is associated with the development of disease complications (cerebral malaria, severe disease, hypotension, among others) (Sanni et al, 1998;Hansen et al, 2000;Tetsutani et al, 2007;Wang et al, 2010;Woodberry et al, 2017).…”

Section: Discussionmentioning

confidence: 54%

“…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: 94%

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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Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

Cited by 43 publications

References 78 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

Mining the Human Host Metabolome Toward an Improved Understanding of Malaria Transmission

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

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