title: Transcriptional analysis of murine macrophages infected with different Toxoplasma strains identifies novel regulation of host signaling pathways.
abstract: Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Mariane B
authors.initials: MB
authors.lastname: Melo
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Quynh P
authors.initials: QP
authors.lastname: Nguyen
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America ; Internal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil ; Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cordeiro
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Musa A
authors.initials: MA
authors.lastname: Hassan
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Ninghan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Renée
authors.initials: R
authors.lastname: McKell
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Rosowski
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Julien
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Butty
authors.affiliation: Centre National de Référence Toxoplasmose/Toxoplasma Biological Resource Center, Centre Hospitalier-Universitaire Dupuytren, Limoges, France ; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1094, Neuroépidémiologie Tropicale, Laboratoire de Parasitologie-Mycologie, Faculté de Médecine, Université de Limoges, Limoges, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Dardé
authors.affiliation: Centre National de Référence Toxoplasmose/Toxoplasma Biological Resource Center, Centre Hospitalier-Universitaire Dupuytren, Limoges, France ; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1094, Neuroépidémiologie Tropicale, Laboratoire de Parasitologie-Mycologie, Faculté de Médecine, Université de Limoges, Limoges, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ajzenberg
authors.affiliation: University of Massachusetts Medical School, Division of Infectious Diseases and Immunology, Worcester, Massachusetts, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lucy H
authors.initials: LH
authors.lastname: Young
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006790:Host-Parasite Interactions / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D015398:Signal Transduction / Q000235:genetics; D014122:Toxoplasma / Q000472:pathogenicity*