Parasite-Derived Neurotrophic Factor/trans-Sialidase of Trypanosoma cruzi Links Neurotrophic Signaling to Cardiac Innate Immune Response

Abstract

The Chagas' disease parasite Trypanosoma cruzi elicits a potent inflammatory response in acutely infected hearts that keeps parasitism in check and triggers cardiac abnormalities. A most-studied mechanism underlying innate immunity in T. cruzi infection is Toll-like receptor (TLR) activation by lipids and other parasite molecules. However, yet-to-be-identified pathways should exist. Here, we show that T. cruzi strongly upregulates monocyte chemoattractant protein 1 (MCP-1)/CCL2 and fractalkine (FKN)/CX3CL1 in cellular and mouse models of heart infection. Mechanistically, upregulation of MCP-1 and FKN stems from the interaction of parasite-derived neurotrophic factor (PDNF)/trans-sialidase with neurotrophic receptors TrkA and TrkC, as assessed by pharmacological inhibition, neutralizing antibodies, and gene silencing studies. Administration of a single dose of intravenous PDNF to naive mice results in a dose-dependent increase in MCP-1 and FKN in the heart and liver with pulse-like kinetics that peak at 3 h postinjection. Intravenous PDNF also augments MCP-1 and FKN in TLR signaling-deficient MyD88-knockout mice, underscoring the MyD88-independent action of PDNF. Although single PDNF injections do not increase MCP-1 and FKN receptors, multiple PDNF injections at short intervals up the levels of receptor transcripts in the heart and liver, suggesting that sustained PDNF triggers cell recruitment at infection sites. Thus, given that MCP-1 and FKN are chemokines essential to the recruitment of immune cells to combat inflammation triggers and to enhance tissue repair, our findings uncover a new mechanism in innate immunity against T. cruzi infection mediated by Trk signaling akin to an endogenous inflammatory and fibrotic pathway resulting from cardiomyocyte-TrkA recognition by matricellular connective tissue growth factor (CTGF/CCN2).

Trypanosoma cruzitrans-Sialidase Prevents Elicitation of Th1 Cell Response via Interleukin 10 and Downregulates Th1 Effector Cells

“…The concerted action of the interplay of these cytokines will delay the induction of a protective Th1 response and dampen these cells once elicited, thus favoring parasite persistence and host colonization. Notably, it was recently reported that TS upregulates the expression of monocyte chemotactic protein 1 (MCP-1/CCL2) and fractalkine (CX3CL1), which are associated with reduction of inflammation and enhancement of tissue repair (55). Thus, TS seems to be able to manipulate both the innate and adaptive immune responses to control the damage to infected tissue caused by the protective Th1 response.…”

Effect of theTc13Tul antigen fromTrypanosoma cruzion splenocytes fromnaïvemice

“…Tc 13Tul also induced polyclonal non-specific Ig stimulation by in vivo administration. It is worth mentioning that, based on previous studies on Tc TS (Da Silva et al ., 1998; Gao et al ., 2002; Aridgides et al ., 2013; Salvador et al ., 2014), in vivo administration of Tc 13Tul was carried out in the absence of any adjuvant that could mask or potentiate its effect. Tc 13Tul-administered mice showed increased non-specific IgG in sera from day 8 post-inoculation and increased total Ig secretion when their splenocytes were in vitro cultured for 72 h. Neither of these antibodies showed specificity for Tc 13Tul or MBP.…”

MyD88 activation in cardiomyocytes contributes to the heart immune response to acute Trypanosoma cruzi infection with no effect on local parasite control

“…At this respect, it has been shown that purified trans-sialidase of T . cruzi activates newborn cardiomyocytes in vitro through a MyD88-independent pathway, resulting in production of the chemokines MCP-1 and Fractalkine [ 44 ].…”