Innate immune activation induces kynurenine pathway and increases T regulatory cells in malaria

Background: Malaria remains a major public health problem in Brazil where Plasmodium vivax (Pv) is the predominant species. An inappropriate immune response to parasite infection is one of the primary drivers of malaria pathogenesis. Regulatory T cells (Tregs, CD4+CD25+FoxP3+CD127-), an important subset of CD4(+) T cells are increased in acute Plasmodium infections, however there is little consensus about their role in malaria immunopathology. On the other hand, indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYU), is driven in part by inflammation and naive T cells are polarized into FoxP3+ Treg cells upon exposure to either IDO+ cells or kynurenine. However, role of kynurenine pathway in Treg induction and malaria pathogenesis has not been studied. Materials and Methods: TRP, KYU, proinflammatory cytokines, monocytes and T cell frequencies were quantified in Pv-infected patients or in vitro stimulated PBMCs. To understand regulatory networks that activate IDO, healthy donor PBMCs were stimulated in vitro with Pv-infected erythrocyte (Pv-iE) lysates in presence or absence of inhibitors for kynurenine and innate signaling pathways. Results: Pv infected patients had a significant increase in plasma IDO activity or KYU/TRP ratio accompanied by increase in Treg cells in acute phase of the disease. This IDO activity was positively correlated with IFN- levels. Moreover, individuals with first Pv infection had comparatively higher KYU/TRP ratio compared to individuals with more than one malaria infection. In vitro stimulation of PBMCs with Pv-iE lysate increased IDO-1 expression in CD14+ cells, KYU/TRP ratio and proinflammatory cytokines. Furthermore, in presence of IDO inhibitor (1-MT) a decrease in KYU/TRP ratio, IDO-1 enzyme expression and Treg cell frequencies was observed upon Pv-iE lysate stimulation. In addition, inhibition of MyD88 decreased KYU/TRP ratio, IDO-1 enzyme expression and Treg cell frequencies in presence of Pv-iE lysate. Conclusion: Innate immune activation via MyD88 induces kynurenine pathway and increases Treg frequencies in Pv infection, which suppresses T effector cell response and hampers parasite clearance.