Abstract
The intracellular protozoan Leishmania replicates in parasitophorous vacuoles (PV) that share many features with late endosomes/lysosomes. L. amazonensis PVs expand markedly during infections, but the impact of PV size on parasite intracellular survival is still unknown. Here we show that host cells infected with L. amazonensis upregulate transcription of LYST/Beige, which was previously shown to regulate lysosome size. Mutations in LYST/Beige caused further PV expansion and enhanced L. amazonensis replication. In contrast, LYST/Beige overexpression led to small PVs that did not sustain parasite growth. Treatment of LYST/Beige over-expressing cells with vacuolin-1 reversed this phenotype, expanding PVs and promoting parasite growth. The opposite was seen with E-64d, which reduced PV size in LYST-Beige mutant cells and inhibited L. amazonensis replication. Enlarged PVs appear to protect parasites from oxidative damage, since inhibition of nitric oxide synthase had no effect on L. amazonensis viability within large PVs, but enhanced their growth within LYST/Beige-induced small PVs. Thus, the upregulation of LYST/Beige in infected cells functions as a host innate response to limit parasite growth, by reducing PV volume and inhibiting intracellular survival.
Highlights
Infections with the trypanosomatid protozoan Leishmania cause a broad spectrum of human diseases throughout the world
We found that the host cell responds to infection with Leishmania amazonensis by upregulating expression of LYST/Beige, a gene that regulates the size of lysosomes and of parasite-containing vacuoles
The parasites replicated more efficiently in the large vacuoles formed in cells that have a mutation in LYST/Beige, whereas the same cells overexpressing functional LYST/Beige generated small vacuoles that were not able to sustain parasite growth
Summary
Infections with the trypanosomatid protozoan Leishmania cause a broad spectrum of human diseases throughout the world. Macrophages are considered the major host cell type for Leishmania, fibroblasts harbor parasites and are thought to play an important role during latent infections [1]) In both macrophages and fibroblasts, intracellular amastigotes replicate within parasitophorous vacuoles (PV) that share several properties with late endosomes/lysosomes, including low luminal pH and the presence of lysosome-specific membrane proteins and acidic hydrolases [2,3]. An important question in the study of Leishmania pathogenesis is how parasites persist indefinitely in the host, even after the development of immunity to reinfection [4] Their exclusively intracellular life style suggests that amastigotes possess mechanisms to avoid killing by the abundant microbicidal products produced by activated host cells. Human mutations in LYST ( known as lysosomal trafficking regulator) are responsible for the Chediak-Higashi syndrome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
