Inflammatory and Pro-resolving Lipids in Trypanosomatid Infections: A Key to Understanding Parasite Control

Abstract

Pathogenic trypanosomatids (Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp.) are protozoan parasites that cause neglected diseases affecting millions of people in Africa, Asia, and the Americas. In the process of infection, trypanosomatids evade and survive the immune system attack, which can lead to a chronic inflammatory state that induces cumulative damage, often killing the host in the long term. The immune mediators involved in this process are not entirely understood. Most of the research on the immunologic control of protozoan infections has been focused on acute inflammation. Nevertheless, when this process is not terminated adequately, permanent damage to the inflamed tissue may ensue. Recently, a second process, called resolution of inflammation, has been proposed to be a pivotal process in the control of parasite burden and establishment of chronic infection. Resolution of inflammation is an active process that promotes the normal function of injured or infected tissues. Several mediators are involved in this process, including eicosanoid-derived lipids, cytokines such as transforming growth factor (TGF)-β and interleukin (IL)-10, and other proteins such as Annexin-V. For example, during T. cruzi infection, pro-resolving lipids such as 15-epi-lipoxin-A4 and Resolvin D1 have been associated with a decrease in the inflammatory changes observed in experimental chronic heart disease, reducing inflammation and fibrosis, and increasing host survival. Furthermore, Resolvin D1 modulates the immune response in cells of patients with Chagas disease. In Leishmania spp. infections, pro-resolving mediators such as Annexin-V, lipoxins, and Resolvin D1 are related to the modulation of cutaneous manifestation of the disease. However, these mediators seem to have different roles in visceral or cutaneous leishmaniasis. Finally, although T. brucei infections are less well studied in terms of their relationship with inflammation, it has been found that arachidonic acid-derived lipids act as key regulators of the host immune response and parasite burden. Also, cytokines such as IL-10 and TGF-β may be related to increased infection. Knowledge about the inflammation resolution process is necessary to understand the host-parasite interplay, but it also offers an interesting opportunity to improve the current therapies, aiming to reduce the detrimental state induced by chronic protozoan infections.

Keywords: Leishmania spp.; Trypanosoma brucei spp.; Trypanosoma cruzi; leukotrienes; lipoxins; prostaglandins; resolution of inflammation; resolvins.

FIGURE 1

Biosynthetic pathways of specialized pro-resolving mediators.

FIGURE 2

Overview of the regulation of inflammatory arachidonic acid (AA) derivatives after Leishmania major or Leishmania amazonensis infections. Cutaneous leishmaniasis causative parasites (L. major and L. amazonensis) induce the production of AA derivatives with opposite roles, depending on the Leishmania species. In L. major infection models (upper panel) the parasite induces the production of PGE₂ and LTB₄. Also, the expression of the EP₁ and EP₃ receptor is increased. The activation of these receptors by PGE₂ leads to parasite survival. PGE₂ also increases the release of IL-10 by the B1 cells, reducing the phagocytic activity of macrophages. On the other hand, L. amazonensis (lower panel) phagocytosis and killing by macrophages is increased by LTB₄ and PGE₂, and this effect is mediated by the NO• increase. Also, L. amazonensis increase the degranulation of neutrophils, increasing the anti parasitic activity of the immune system.

FIGURE 3

Overview of the regulation of inflammatory arachidonic acid (AA) derivatives after Leishmania infantum or Leishmania donovani infections. Visceral leishmaniasis causative parasites (L. infantum and L. donovani) induce the production of AA derivatives with opposite roles, depending of the Leishmania species. L. infantum infection (right panel) induce the release of TNF-α, IL-12, MCP-1 and PGE₂ from macrophages. PGE₂, in turn, induce the production of NO•, enhancing parasite killing. In contrast, L. donovani (left panel) increase the production of PGE₂ by magrophages, through the activation of the PI₃K pathway and the NFAT2 transcription factor. This augmented PGE₂ activates the EP₂ receptor in macrophages, inducing the release of regulatory cytokines such as TGF-β and IL-10, thus impairing the immune response against the parasite.