biostudies-literatureOkuda KNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSNational Institutes of Health104909https://www.ebi.ac.uk/biostudies/studies/S-EPMC9436752biostudies-literatureUnknown25(9)<i>Leishmania</i> 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 <i>Drosophila</i> macrophage-like cells to identify the host factors necessary for <i>Leishmania amazonensis</i> 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 <i>L. amazonensis</i> infection inhibited SUMOylation within infected macrophages and this inhibition enhanced parasitophorous vacuole growth and parasite proliferation through modulation of multiple genes especially <i>ATP6V0D2</i>, which in turn affects <i>CD36</i> 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.iScience<i>Leishmania amazonensis</i> sabotages host cell SUMOylation for intracellular survival.PMC9436752R21 AI136532R21AI136532R21 AI154208R21AI154208R21 AI109678R56 AI165847Cherry SSilverman NOkuda KGazzinelli RRabinovitch MYasunaga ASilva Costa Franco MMfalse<i>Leishmania amazonensis</i> sabotages host cell SUMOylation for intracellular survival.<i>Leishmania</i> 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 <i>Drosophila</i> macrophage-like cells to identify the host factors necessary for <i>Leishmania amazonensis</i> 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 <i>L. amazonensis</i> infection inhibited SUMOylation within infected macrophages and this inhibition enhanced parasitophorous vacuole growth and parasite proliferation through modulation of multiple genes especially <i>ATP6V0D2</i>, which in turn affects <i>CD36</i> 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.2022-01-01T00:00:00Z2022 Sep2026-05-28T03:28:12.355Z2025-02-19T00:44:08.191ZS-EPMC94367523606006410.1016/j.isci.2022.104909