Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance

Abstract

Visceral leishmaniasis (VL) remains a major public health problem worldwide. Cytokine balance is thought to play a critical role in the development of this disease. Here, we perform a prospective exploratory study addressing whether simultaneous assessment of circulating levels of different lipid mediators and cytokines could highlight specific pathways involved with VL pathogenesis. VL patients displayed substantial increases in serum levels of Prostaglandin F2α (PGF2α), Leukotriene B4 (LTB4), Resolvin D1 (RvD1), IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α compared with uninfected endemic control group, while exhibiting decreased levels of TGF-β1. Hierarchical cluster analysis of the prospective changes in the expression level of theses parameters upon anti-Leishmania treatment initiation revealed that the inflammatory profile observed in active disease gradually changed over time and was generally reversed at day 30 of therapy. Furthermore, not only the individual concentrations of most of the inflammatory biomarkers changed upon treatment, but the correlations between those and several biochemical parameters used to characterize VL disease activity were also modified over time. These results demonstrate that an inflammatory imbalance hallmarks active VL disease and open perspective for manipulation of these pathways in future studies examining a potential host-directed therapy against VL.

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

“…This finding suggests that L. major -infected macrophages probably evolved the ability to inhibit a deleterious innate inflammatory immune response (Fleming et al, 2015 ); alternatively, this anti-inflammatory response could be a consequence of the effort by host macrophages to control parasite infection (Dillon et al, 2015 ). Consistent with these findings, in the sera of patients during the active phase of visceral leishmaniasis it was detected a significant increase in inflammatory mediators including LTB4, RvD1, PGF2α (PGF2α), IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α, and a decreased level of TGF-β1 (Araújo-Santos et al, 2017 ).…”

“…The identification of a set of soluble biomarkers in host tissue has been exploited using sera of individuals with visceral leishmaniasis (Solcà et al, 2016 ; Araújo-Santos et al, 2017 ). A recent study screened a variety of soluble molecules and identified a set of inflammatory biomarkers that grouped together under a hierarchical cluster analysis (Araújo-Santos et al, 2017 ).…”

“…The identification of a set of soluble biomarkers in host tissue has been exploited using sera of individuals with visceral leishmaniasis (Solcà et al, 2016 ; Araújo-Santos et al, 2017 ). A recent study screened a variety of soluble molecules and identified a set of inflammatory biomarkers that grouped together under a hierarchical cluster analysis (Araújo-Santos et al, 2017 ). A significant increase in the levels of the following inflammatory mediators was observed: resolvin D1 (RvD1), leukotriene B4 (LTB4), prostaglandin F2α (PGF2α), IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α, in contrast to a decrease in TGF-β1 in the serum of patients with visceral leishmaniasis compared with an uninfected endemic control group.…”

“…After 30 days of therapy, the authors observed that individuals clustered together in terms of decreases in the levels of these inflammatory molecules, distinct from the individuals with active infection, thus reinforcing the idea that this set of soluble molecules might function as biomarkers for the host response to therapy. These authors further remarked that the modulation observed in the concentrations of these markers provides evidence that “an inflammatory imbalance hallmarks active visceral leishmaniasis disease,” which more importantly can greatly aid in the design of new interventions (Araújo-Santos et al, 2017 ). Another recent study focused on the identification of circulating biomarkers of “inflammation, immune activation, oxidative stress, and anti-sand fly saliva IgG concentrations” in canine sera to characterize biosignatures associated with the severity of visceral leishmaniasis in dogs presenting a variety of clinical manifestations (Solcà et al, 2016 ).…”

Phenotypical Characterization of Spleen Remodeling in Murine Experimental Visceral Leishmaniasis

“…The disease results from an inability of macrophages to kill the parasite (6). A complex signaling network of molecules produced by macrophages and T and B lymphocytes, with pro-and anti-inflammatory roles, produces an inflammatory status that is responsible for the many clinical manifestations of the disease without achieving control of parasite growth (5,7). The bone marrow, liver and spleen are the most affected internal organs (8).…”