Insights into malaria pathogenesis gained from host metabolomics

Colvin, Heather N.; Cordy, Regina Joice

doi:10.1371/journal.ppat.1008930

Cited by 20 publications

(14 citation statements)

References 49 publications

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“…Both hosts had lower Trp and higher Kyn levels in the peripheral blood during the log and peak phases of infection in comparison with baseline levels (TP1 and TP2), as observed previously with P. coatneyi infection of rhesus macaques ( Cordy et al, 2019 ; Colvin and Joice Cordy, 2020 ). Of special note here, however, is that the Kyn/Trp ratio, a known inflammatory biomarker, is reduced in Mf near peak infection, whereas it remains at the same level as during the log phase in Mm ( Figure 4 ).…”

Section: Resultssupporting

confidence: 82%

“…Another known inflammation biomarker, the Kyn/Trp ratio, shows surprisingly deep integration with these processes. Even though the induction of IDO in malarial infection is quite often discussed ( Sanni et al, 1998 ; Hansen et al, 2000 ; Tetsutani et al, 2007 ; Colvin and Joice Cordy, 2020 ; Santos et al, 2020 ), its biological significance for the immune response is in general poorly understood. Nonetheless, a mathematical model of the direct upregulation of IDO through IFNγ signaling quite clearly shows how the Kyn/Trp ratio changes during the infection ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

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Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

Gupta

Galinski

Voit

2022

Front. Mol. Biosci.

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Malaria has a complex pathology with varying manifestations and symptoms, effects on host tissues, and different degrees of severity and ultimate outcome, depending on the causative Plasmodium pathogen and host species. Previously, we compared the peripheral blood transcriptomes of two macaque species (Macaca mulatta and Macaca fascicularis) in response to acute primary infection by Plasmodium knowlesi. Although these two species are very closely related, the infection in M. mulatta is fatal, unless aggressively treated, whereas M. fascicularis develops a chronic, but tolerable infection in the blood. As a reason for this stark difference, our analysis suggests delayed pathogen detection in M. mulatta followed by extended inflammation that eventually overwhelms this monkey’s immune response. By contrast, the natural host M. fascicularis detects the pathogen earlier and controls the inflammation. Additionally, M. fascicularis limits cell proliferation pathways during the log phase of infection, presumably in an attempt to control inflammation. Subsequent cell proliferation suggests a cell-mediated adaptive immune response. Here, we focus on molecular mechanisms underlying the key differences in the host and parasite responses and their coordination. SICAvar Type 1 surface antigens are highly correlated with pattern recognition receptor signaling and important inflammatory genes for both hosts. Analysis of pathogen detection pathways reveals a similar signaling mechanism, but with important differences in the glutamate G-protein coupled receptor (GPCR) signaling pathway. Furthermore, differences in inflammasome assembly processes suggests an important role of S100 proteins in balancing inflammation and cell proliferation. Both differences point to the importance of Ca2+ homeostasis in inflammation. Additionally, the kynurenine-to-tryptophan ratio, a known inflammatory biomarker, emphasizes higher inflammation in M. mulatta during log phase. Transcriptomics-aided metabolic modeling provides a functional method for evaluating these changes and understanding downstream changes in NAD metabolism and aryl hydrocarbon receptor (AhR) signaling, with enhanced NAD metabolism in M. fascicularis and stronger AhR signaling in M. mulatta. AhR signaling controls important immune genes like IL6, IFNγ and IDO1. However, direct changes due to AhR signaling could not be established due to complicated regulatory feedback mechanisms associated with the AhR repressor (AhRR). A complete understanding of the exact dynamics of the immune response is difficult to achieve. Nonetheless, our comparative analysis provides clear suggestions of processes that underlie an effective immune response. Thus, our study identifies multiple points of intervention that are apparently responsible for a balanced and effective immune response and thereby paves the way toward future immune strategies for treating malaria.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

Gupta

Galinski

Voit

2022

Front. Mol. Biosci.

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“…Glutamine, for instance, plays a major role in the immune system, as a key energy source for immune cells and it is used at a higher rate during catabolic conditions such as sepsis or other infections [27]. Depletion of glutamine and also citrulline identified in this study could also be used as indicators of disease severity as suggested in [38]. Decreased oxoproline levels were also previously associated with a non-infectious fever-associated disease, Rheumatoid Arthritis [39].…”

Section: Discussionmentioning

confidence: 93%

Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites

Năstase

Barrett

Cárdenas

et al. 2021

Preprint

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Acute febrile illnesses are still a major cause of mortality and morbidity globally, particularly in low to middle income countries. The aim of this study was to determine any possible metabolic commonalities of patients infected with disparate pathogens that cause fever. Three liquid chromatography-mass spectrometry (LC-MS) datasets investigating the metabolic effects of malaria, leishmaniasis and Zika virus infection were used. The retention time (RT) drift between the datasets was determined using landmarks obtained from the standard reference mixtures generally used in the quality control of the LC-MS experiments. We used fitted Gaussian Process models (GPs) to perform a high level correction of the RT drift between the experiments, followed by standard peakset alignment between the samples with corrected RTs of the three LC-MS datasets. Statistical analysis, annotation and pathway analysis of the integrated peaksets were subsequently performed. Metabolic dysregulation patterns common across the datasets were identified, with kynurenine pathway being the most affected pathway between all three fever-associated datasets.

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“…For example, Kynurenine-AhR signaling has been investigated towards suppressing the anti-tumor immune response and promoting tumor growth (Gunther et al, 2020; Opitz et al, 2011; Prendergast, 2011; Xue et al, 2018), yielding IDO-1 inhibitors as promising candidates for cancer therapy (Diray-Arce et al, 2022; Vacchelli et al, 2014; Zhai et al, 2015). On the other hand, Kynurenine-AhR signaling has been found to generate regulatory T-cells and inhibiting the Th1 response (Campesato et al, 2020; Fallarino et al, 2006) in viral (Adu-Gyamfi et al, 2019; Fox et al, 2013; Mehraj and Routy, 2015) and parasitic (Colvin and Joice Cordy, 2020; Cordy et al, 2019; Dos Santos et al, 2020; Majumdar et al, 2019; Schmidt and Schultze, 2014) diseases, including Malaria, Toxoplasma gondii , and Influenza.…”

Section: Discussionmentioning

confidence: 99%

Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response

Oljuskin

Azodi²,

Volpedo

et al. 2022

Preprint

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Leishmaniasis is a parasitic disease that is prevalent in approximately 88 countries, and yet no licensed human vaccine exists against it. Towards control of leishmaniasis, we have developed Leishmania major Centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong Th1 response to provide IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania-infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen-/- and compared with virulent L. major parasite infection to identify the immune mechanism of protection. Our data shows that immunization with LmCen-/- parasites, in contrast to virulent L. major infection, alters tryptophan metabolism to down-regulate Kynurenine-AhR signaling and promote a pro-inflammatory response.

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Insights into malaria pathogenesis gained from host metabolomics

Cited by 20 publications

References 49 publications

Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites

Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response

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