14 junio 2019

ATP6V0d2 controls Leishmania parasitophorous vacuole biogenesis via cholesterol homeostasis.

DOI : 10.1371/journal.ppat.1007834

Cristian Cortez

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.

Investigadores Participantes del Centro

Host-Pathogen Interactions Laboratory

Doctor en Ciencias, Mención Microbiología, Inmunología y Parasitología, Universidad Federal de Sao Paulo, Brasil.



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