Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria

Tran, Tuan M.; Jones, Marcus B.; Ongoïba, Aïssata; Bijker, Else M.; Schats, Remko; Venepally, Pratap; Skinner, Jeff; Doumbo, Safiatou; Quinten, Edwin; Visser, Leo G.; Whalen, Elizabeth; Presnell, Scott; O’Connell, Elise M.; Kayentao, Kassoum; Doumbo, Ogobara K.; Chaussabel, Damien; Lorenzi, Hernán; Nutman, Thomas B.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Traoré, Boubacar; Kirkness, Ewen F.; Sauerwein, Robert W.; Crompton, Peter D.

doi:10.1038/srep31291

Cited by 90 publications

(117 citation statements)

References 39 publications

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“…Moreover, the efficacy of IPTp with SP to clear peripheral parasites and prevent new infections during pregnancy has been suggested to be compromised only in areas with > 90% prevalence of Pfdhps K540E mutation [33]. Taken together, these results suggest that immunoregulatory responses that reduce pathogenic inflammation and potentially the risk of anaemia [38] may be developed by pregnant women exposed to P. falciparum , as has been suggested for children [39–41]. …”

Section: Discussionmentioning

confidence: 93%

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

Ndam

Mbuba

González

et al. 2017

BMC Med

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BackgroundResistance and tolerance to Plasmodium falciparum can determine the progression of malaria disease. However, quantitative evidence of tolerance is still limited. We investigated variations in the adverse impact of P. falciparum infections among African pregnant women under different intensities of malaria transmission.Methods P. falciparum at delivery was assessed by microscopy, quantitative PCR (qPCR) and placental histology in 946 HIV-uninfected and 768 HIV-infected pregnant women from Benin, Gabon, Kenya and Mozambique. Resistance was defined by the proportion of submicroscopic infections and the levels of anti-parasite antibodies quantified by Luminex, and tolerance by the relationship of pregnancy outcomes with parasite densities at delivery.Results P. falciparum prevalence by qPCR in peripheral and/or placental blood of HIV-uninfected Mozambican, Gabonese and Beninese women at delivery was 6% (21/340), 11% (28/257) and 41% (143/349), respectively. The proportion of peripheral submicroscopic infections was higher in Benin (83%) than in Mozambique (60%) and Gabon (55%; P = 0.033). Past or chronic placental P. falciparum infection was associated with an increased risk of preterm birth in Mozambican newborns (OR = 7.05, 95% CI 1.79 to 27.82). Microscopic infections were associated with reductions in haemoglobin levels at delivery among Mozambican women (–1.17 g/dL, 95% CI –2.09 to –0.24) as well as with larger drops in haemoglobin levels from recruitment to delivery in Mozambican (–1.66 g/dL, 95% CI –2.68 to –0.64) and Gabonese (–0.91 g/dL, 95% CI –1.79 to –0.02) women. Doubling qPCR-peripheral parasite densities in Mozambican women were associated with decreases in haemoglobin levels at delivery (–0.16 g/dL, 95% CI –0.29 to –0.02) and increases in the drop of haemoglobin levels (–0.29 g/dL, 95% CI –0.44 to –0.14). Beninese women had higher anti-parasite IgGs than Mozambican women (P < 0.001). No difference was found in the proportion of submicroscopic infections nor in the adverse impact of P. falciparum infections in HIV-infected women from Kenya (P. falciparum prevalence by qPCR: 9%, 32/351) and Mozambique (4%, 15/417).ConclusionsThe lowest levels of resistance and tolerance in pregnant women from areas of low malaria transmission were accompanied by the largest adverse impact of P. falciparum infections. Exposure-dependent mechanisms developed by pregnant women to resist the infection and minimise pathology can reduce malaria-related adverse outcomes. Distinguishing both types of defences is important to understand how reductions in transmission can affect malaria disease.Trial registrationClinicalTrials.gov NCT00811421. Registered 18 December 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0893-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 93%

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

Ndam

Mbuba

González

et al. 2017

BMC Med

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“…There are some exciting new areas of research that have begun to be explored in malaria. As mentioned above, remarkable discoveries are being made using multiparameter methods, transcriptomics and unbiased computational analyses of human immune responses . A logical progression would be to determine the influence of epigenetic modifications, such as DNA methylation and chromatin remodelling that regulate immune cell gene expression .…”

Section: New Areas Of Investigation and New Analytical Approachesmentioning

confidence: 99%

“…As mentioned above, remarkable discoveries are being made using multiparameter methods, transcriptomics and unbiased computational analyses of human immune responses. 156 A logical progression would be to determine the influence of epigenetic modifications, such as DNA methylation and chromatin remodelling that regulate immune cell gene expression. 157 In addition, the role of noncoding RNA (both human and P. falciparum-derived) is a rich area of exploration in human immunology.…”

Section: Ne W Are a S Of Inve S Ti G Ati On And Ne W Analy Tic Al Amentioning

confidence: 99%

Immune effector mechanisms in malaria: An update focusing on human immunity

Moormann

Nixon

Forconi

2019

Parasite Immunology

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The past decade has witnessed dramatic decreases in malaria‐associated mortality and morbidity around the world. This progress has largely been due to intensified malaria control measures, implementation of rapid diagnostics and establishing a network to anticipate and mitigate antimalarial drug resistance. However, the ultimate tool for malaria prevention is the development and implementation of an effective vaccine. To date, malaria vaccine efforts have focused on determining which of the thousands of antigens expressed by Plasmodium falciparum are instrumental targets of protective immunity. The antigenic variation and antigenic polymorphisms arising in parasite genes under immune selection present a daunting challenge for target antigen selection and prioritization, and is a given caveat when interpreting immune recall responses or results from monovalent vaccine trials. Other immune evasion strategies executed by the parasite highlight the myriad of ways in which it can become a recurrent infection. This review provides an update on immune effector mechanisms in malaria and focuses on our improved ability to interrogate the complexity of human immune system, accelerated by recent methodological advances. Appreciating how the human immune landscape influences the effectiveness and longevity of antimalarial immunity will help explain which conditions are necessary for immune effector mechanisms to prevail.

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“…Malaria infection inflicts host pathology by immune activation and increasing several proinflammatory mediators during the acute phase of the disease, whereas the host tries to circumvent these deleterious effects by increasing tolerance mechanisms to avoid tissue damage . The increase of tolerogenic FoxP3+ T regulatory cell (Treg) has been described in acute murine and human malaria infections .…”

Section: Introductionmentioning

confidence: 99%

“…Malaria infection inflicts host pathology by immune activation and increasing several proinflammatory mediators during the acute phase of the disease, [7][8][9][10] whereas the host tries to circumvent these deleterious effects by increasing tolerance mechanisms to avoid tissue damage. 10,11 The increase of tolerogenic FoxP3+ T regulatory cell (Treg) has been described in acute murine and human malaria infections. [12][13][14] Recent studies demonstrated that kynurenines (KYN), products of the tryptophan (TRP) catabolism pathway, induce the generation of Tregs via the activation of the aryl hydrocarbon receptor (AhR).…”

mentioning

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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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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Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria

Cited by 90 publications

References 39 publications

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities

Immune effector mechanisms in malaria: An update focusing on human immunity

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

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