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Quantification of Intracellular Growth Inside Macrophages is a Fast and Reliable Method for Assessing the Virulence of Leishmania Parasites
Published on: March 16, 2018
Leishmania amazonensis sabotages host cell SUMOylation for intracellular survival
Kendi Okuda1, Miriam Maria Silva Costa Franco1, Ari Yasunaga2
1Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA.
Abstract:
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.
Insights
Leishmania parasites sabotage host SUMOylation to boost their growth inside macrophages. This manipulation enhances parasite replication by altering host cell genes and creating a better intracellular niche.
Area of Science:
- Cell Biology
- Parasitology
- Immunology
Background:
- Leishmania parasites employ sophisticated virulence strategies to infect macrophages, inhibiting host defenses and establishing a replicative niche called the parasitophorous vacuole.
- Understanding host factors crucial for Leishmania infection is vital for developing targeted therapies.
Purpose of the Study:
- To identify host factors essential for Leishmania amazonensis infection using a genome-wide RNA interference (RNAi) screen.
- To investigate the role of SUMOylation in Leishmania infection and its impact on the host cell.
Main Methods:
- A genome-wide RNAi screen was conducted in Drosophila macrophage-like cells to identify host genes involved in Leishmania amazonensis entry.
- Subsequent studies in mammalian macrophages analyzed the effects of L. amazonensis infection on SUMOylation and host gene expression.
Main Results:
- The screen identified 52 conserved genes critical for parasite entry, including components of the SUMOylation pathway.
- Leishmania amazonensis infection was found to inhibit SUMOylation in macrophages, promoting parasitophorous vacuole growth and parasite proliferation.
- This inhibition modulated host genes, notably ATP6V0D2, influencing CD36 expression and cholesterol levels.
Conclusions:
- Leishmania parasites actively disrupt host SUMOylation processes to optimize their intracellular environment.
- Altering host transcription, particularly affecting ATP6V0D2 and CD36, is a key mechanism by which parasites enhance their replication within macrophages.
