title: 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).
authors.affiliation: Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, and Department of Developmental, Biochemical and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Salvador
authors.affiliation: Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, and Department of Developmental, Biochemical and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aridgides
authors.affiliation: Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, and Department of Developmental, Biochemical and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA Mercio.perrin@tufts.edu.
authors.forename: Mercio
authors.initials: M
authors.lastname: PereiraPerrin
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology / Q000469:parasitology; D018932:Chemokine CCL2 / Q000276:immunology; D054428:Chemokine CX3CL1 / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D057809:HEK293 Cells; D006321:Heart / Q000469:parasitology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009439:Neuraminidase / Q000276:immunology*; D051381:Rats; D015398:Signal Transduction / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D006023:Glycoproteins; D053594:Myeloid Differentiation Factor 88; C069715:trans-sialidase; D009439:Neuraminidase