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.

Although with intact mucosa at colonoscopy, chagasic megacolons have an overexpression of Gal-3

“…(17) In the present study, chagasic patients (CML+CIM), who also presented with a higher density of Gal-3, showed a percentage of collagen significantly greater than the NC Group, which corroborates the literature, since it has already been demonstrated in mice that T. cruzi can be the factor direct or indirectly responsible for molecular modification in different tissues and organs, enabling the induction of cell lesions, inflammatory response, and fibrosis mediated by Gal-3. (27) Nonetheless, our study was the first to associate Gal-3 with fibrosis in Chagas disease in humans.…”

Immunometabolism of Leishmania granulomas

“…PPAR-c-d are activated by anti-inflammatory cytokines (IL-4, IL-13, IL-10), TLR receptors and a range of lipids and other stimuli, including oxidized low-density lipoprotein, PUFA (arachidonic acid, 5hydroxyeicosatetraenoic acid and 5-oxo-eicosatetraenoic acid), oxidized linoleic acid (13-HODE) and prostaglandins (D2, prostaglandin E2, prostaglandin F2, thromboxane B2), that are variously present in Leishmania granulomatous tissues. 83 Interestingly, Leishmania-derived PUFAs polarize murine macrophages toward an M2 phenotype when added exogenously. 84 As noted earlier, Leishmania amastigotes form a tight junction with the PVM, raising the possibility that parasite lipids may be directly transported to the host cell and modulate host cell signaling.…”

Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

“…However, the in vivo cellular source of IL-10 and the window within which these cells exert their function during the course of African trypanosomiasis, as well as the associated molecular mechanism(s) implicated in its production, remain poorly understood. Hence, knowledge about the inflammation resolution process is necessary to understand the host-parasite interplay and might pave the way to improve or develop more efficient therapies that reduce the devastating effect of chronic protozoan infections [21].…”