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

Abstract

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.

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

“…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). 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.…”

Host 5-HT affectsPlasmodiumtransmission in mosquitoes via modulating mosquito mitochondrial homeostasis

“…Malaria parasites are known to suppress host immune responses by inducing the expression of indoleamine 2,3 dioxygenase (IDO), which is the rate-limiting enzyme of the kynurenine pathway in mammals. [34][35][36] The metabolites along the kynurenine pathway have been implicated in the pathogenesis of murine and human cerebral malaria. 37 The shift in tryptophan metabolism towards the kynurenine pathway may lead to the reduction of 5-HT production.…”

IWP‐2 modulates the immunomodulatory properties of human dental pulp stem cells in vitro

“…IDO serves as a rate-limiting enzyme in tryptophan metabolism, leading to the production of kynurenine. Elevated levels of kynurenine resulting from IDO activity have been shown to inhibit T cell proliferation (Fallarino et al, 2003), and promote the differentiation of Tregs (Forteza et al, 2018). Furthermore, an overexpression of IDO has been linked to the enhanced polarization of THP1 cells into M2 macrophages (Dos Santos et al, 2020;Mezrich et al, 2010).…”

“…Elevated levels of kynurenine resulting from IDO activity have been shown to inhibit T cell proliferation (Fallarino et al., 2003), and promote the differentiation of Tregs (Forteza et al., 2018). Furthermore, an overexpression of IDO has been linked to the enhanced polarization of THP1 cells into M2 macrophages (Dos Santos et al., 2020; Mezrich et al., 2010). In the context of hDPSCs, IDO plays a role in regulating an immunosuppressive phenotype that inhibits the proliferation of peripheral blood mononuclear cells (PBMCs) (Hossein‐khannazer et al., 2019; Tomic et al., 2011).…”