ATP6V0d2 Controls Leishmania Parasitophorous Vacuole Biogenesis Via Cholesterol Homeostasis

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2019 Jun 15

PMID 31199856

Citations 14

Authors

Carina Carraro Pessoa

Luiza Campos Reis

Eduardo Milton Ramos-Sanchez

Cristina Mary Orikaza

Cristian Cortez

Erica Valadares de Castro Levatti

Ana Carolina Benites Badaro

Joyce Umbelino da Silva Yamamoto

Vania DAlmeida

Hiro Goto

Renato Arruda Mortara

Fernando Real

Affiliations

Soon will be listed here.

Abstract

V-ATPases are part of the membrane components of pathogen-containing vacuoles, although their function in intracellular infection remains elusive. In addition to organelle acidification, V-ATPases are alternatively implicated in membrane fusion and anti-inflammatory functions controlled by ATP6V0d2, the d subunit variant of the V-ATPase complex. Therefore, we evaluated the role of ATP6V0d2 in the biogenesis of pathogen-containing vacuoles using ATP6V0d2 knock-down macrophages infected with the protozoan parasite Leishmania amazonensis. These parasites survive within IFNγ/LPS-activated inflammatory macrophages, multiplying in large/fusogenic parasitophorous vacuoles (PVs) and inducing ATP6V0d2 upregulation. ATP6V0d2 knock-down decreased macrophage cholesterol levels and inhibited PV enlargement without interfering with parasite multiplication. However, parasites required ATP6V0d2 to resist the influx of oxidized low-density lipoprotein (ox-LDL)-derived cholesterol, which restored PV enlargement in ATP6V0d2 knock-down macrophages by replenishing macrophage cholesterol pools. Thus, we reveal parasite-mediated subversion of host V-ATPase function toward cholesterol retention, which is required for establishing an inflammation-resistant intracellular parasite niche.

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