title: Dual Transcriptome Profiling of Leishmania-Infected Human Macrophages Reveals Distinct Reprogramming Signatures.
abstract: Macrophages are mononuclear phagocytes that constitute a first line of defense against pathogens. While lethal to many microbes, they are the primary host cells of Leishmania spp. parasites, the obligate intracellular pathogens that cause leishmaniasis. We conducted transcriptomic profiling of two Leishmania species and the human macrophage over the course of intracellular infection by using high-throughput RNA sequencing to characterize the global gene expression changes and reprogramming events that underlie the interactions between the pathogen and its host. A systematic exclusion of the generic effects of large-particle phagocytosis revealed a vigorous, parasite-specific response of the human macrophage early in the infection that was greatly tempered at later time points. An analogous temporal expression pattern was observed with the parasite, suggesting that much of the reprogramming that occurs as parasites transform into intracellular forms generally stabilizes shortly after entry. Following that, the parasite establishes an intracellular niche within macrophages, with minimal communication between the parasite and the host cell later during the infection. No significant difference was observed between parasite species transcriptomes or in the transcriptional response of macrophages infected with each species. Our comparative analysis of gene expression changes that occur as mouse and human macrophages are infected by Leishmania spp. points toward a general signature of the Leishmania-macrophage infectome.
  
  
  
  Little is known about the transcriptional changes that occur within mammalian cells harboring intracellular pathogens. This study characterizes the gene expression signatures of Leishmania spp. parasites and the coordinated response of infected human macrophages as the pathogen enters and persists within them. After accounting for the generic effects of large-particle phagocytosis, we observed a parasite-specific response of the human macrophages early in infection that was reduced at later time points. A similar expression pattern was observed in the parasites. Our analyses provide specific insights into the interplay between human macrophages and Leishmania parasites and constitute an important general resource for the study of how pathogens evade host defenses and modulate the functions of the cell to survive intracellularly.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Fernandes
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA.
authors.forename: Laura A L
authors.initials: LA
authors.lastname: Dillon
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA.
authors.forename: Ashton Trey
authors.initials: AT
authors.lastname: Belew
authors.affiliation: Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA Department of Computer Science, University of Maryland, College Park, Maryland, USA.
authors.forename: Hector Corrada
authors.initials: HC
authors.lastname: Bravo
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Mosser
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA elsayed@umd.edu.
authors.forename: Najib M
authors.identifier: 0000-0001-7970-3312
authors.initials: NM
authors.lastname: El-Sayed
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006790:Host-Parasite Interactions; D006801:Humans; D007891:Leishmania / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D010587:Phagocytosis; D059467:Transcriptome