Leishmania amazonensis sabotages host cell SUMOylation for intracellular survival
Kendi Okuda,
Miriam Maria Silva Costa Franco,
Ari Yasunaga,
Ricardo Gazzinelli,
Michel Rabinovitch,
Sara Cherry,
Neal Silverman
Affiliations
Kendi Okuda
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA
Miriam Maria Silva Costa Franco
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA
Ari Yasunaga
Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Ricardo Gazzinelli
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA; Centro de Tecnologia de Vacinas, Universidade Federal of Minas Gerais, Belo Horizonte, MG 31270, Brazil; Fundação Oswaldo Cruz - Minas, Belo Horizonte, MG 30190, Brazil
Michel Rabinovitch
Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Sara Cherry
Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Neal Silverman
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA; Corresponding author
Summary: Leishmania parasites use elaborate virulence mechanisms to invade and thrive in macrophages. These virulence mechanisms inhibit host cell defense responses and generate a specialized replicative niche, the parasitophorous vacuole. In this work, we performed a genome-wide RNAi screen in Drosophila macrophage-like cells to identify the host factors necessary for Leishmania amazonensis infection. This screen identified 52 conserved genes required specifically for parasite entry, including several components of the SUMOylation machinery. Further studies in mammalian macrophages found that L. amazonensis infection inhibited SUMOylation within infected macrophages and this inhibition enhanced parasitophorous vacuole growth and parasite proliferation through modulation of multiple genes especially ATP6V0D2, which in turn affects CD36 expression and cholesterol levels. Together, these data suggest that parasites actively sabotage host SUMOylation and alter host transcription to improve their intracellular niche and enhance their replication.
