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

Abstract

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.

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

“…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 ).…”

Insights into malaria pathogenesis gained from host metabolomics

“…Elevated kynurenine also indicates elevated indoleamine 2,3-dioxygenase (IDO) enzymatic activity and the initiation of the host’s immunotolerant responses. While tryptophan catabolites may have a neurotoxic role, the catabolism of tryptophan is likely driven by the host’s acute response to malaria, which includes both pro-inflammatory and anti-inflammatory tolerogenic programs [ 31 ].…”

A systematic analysis of the human immune response to Plasmodium vivax

“…The analyte with the lowest FDR was IFN-γ, indicating a robust type I inflammatory response, which has been extensively described in febrile disease (including vivax malaria; refs. 24 , 25 , 27 ). In agreement, analytes associated with the recruitment (CCL2, CXCL9, and CXCL10) and activation (IL-12, IL-18, and IL-21) of inflammatory monocytes and CD4 + T cells were also induced.…”