title: Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy.
abstract: Host and parasite diversity are suspected to be key factors in Chagas disease pathogenesis. Experimental investigation of underlying mechanisms is hampered by a lack of tools to detect scarce, pleiotropic infection foci. We developed sensitive imaging models to track Trypanosoma cruzi infection dynamics and quantify tissue-specific parasite loads, with minimal sampling bias. We used this technology to investigate cardiomyopathy caused by highly divergent parasite strains in BALB/c, C3H/HeN and C57BL/6 mice. The gastrointestinal tract was unexpectedly found to be the primary site of chronic infection in all models. Immunosuppression induced expansion of parasite loads in the gut and was followed by widespread dissemination. These data indicate that differential immune control of T. cruzi occurs between tissues and shows that the large intestine and stomach provide permissive niches for active infection. The end-point frequency of heart-specific infections ranged from 0% in TcVI-CLBR-infected C57BL/6 to 88% in TcI-JR-infected C3H/HeN mice. Nevertheless, infection led to fibrotic cardiac pathology in all models. Heart disease severity was associated with the model-dependent frequency of dissemination outside the gut and inferred cumulative heart-specific parasite loads. We propose a model of cardiac pathogenesis driven by periodic trafficking of parasites into the heart, occurring at a frequency determined by host and parasite genetics.
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. michael.lewis@lshtm.ac.uk.|Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, 20892, USA. michael.lewis@lshtm.ac.uk.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lewis
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Amanda Fortes
authors.initials: AF
authors.lastname: Francisco
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Taylor
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Shiromani
authors.initials: S
authors.lastname: Jayawardhana
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Kelly
mesh_terms: D000659:AMP Deaminase; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000469:parasitology*; D014355:Chagas Disease / Q000235:genetics / Q000469:parasitology*; D005260:Female; D041981:Gastrointestinal Tract / Q000469:parasitology; D017125:Genes, Protozoan; D014644:Genetic Variation; D006790:Host-Parasite Interactions; D008297:Male; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009206:Myocardium / Q000473:pathology; D014349:Trypanosoma cruzi / Q000235:genetics*
chemical_list: D000659:AMP Deaminase