Nutrient sensing in Leishmania: Flagellum and cytosol

Abstract

Parasites are by definition organisms that utilize resources from a host to support their existence, thus, promoting their ability to establish long-term infections and disease. Hence, sensing and acquiring nutrients for which the parasite and host compete is central to the parasitic mode of existence. Leishmania are flagellated kinetoplastid parasites that parasitize phagocytic cells, principally macrophages, of vertebrate hosts and the alimentary tract of sand fly vectors. Because nutritional supplies vary over time within both these hosts and are often restricted in availability, these parasites must sense a plethora of nutrients and respond accordingly. The flagellum has been recognized as an "antenna" that plays a core role in sensing environmental conditions, and various flagellar proteins have been implicated in sensing roles. In addition, these parasites exhibit non-flagellar intracellular mechanisms of nutrient sensing, several of which have been explored. Nonetheless, mechanistic details of these sensory pathways are still sparse and represent a challenging frontier for further experimental exploration.

Fig. 1.

Leishmania parasites and locations of potential sensors. A. Insect stage promastigotes have an extended cell body and a long flagellum that exits from the flagellar pocket. B. Intracellular amastigotes have on oval-shaped cell body and a short flagellum that barely emerges from the flagellar pocket. In both life cycle stages, membrane bound sensors could be located at the distal tip of the flagellum (red sphere), along the length of the flagellum (purple sphere), or on the cell body membrane (green sphere), and other sensors could be cytosolic proteins (blue sphere). C. A cross section of the flagellum shows the surrounding flagellar membrane and an integral membrane protein (purple) representing a putative flagellar sensor. Other components of all images are as labeled. This figure was prepared by Laramie Studio, Portland, OR.

Fig. 2.

Localization of three proteins with potential roles in signaling to different components of the flagellar membrane in L. mexicana promastigotes. A) The flagellar glucose transporter GT1, tagged at the C-terminus with GFP, localizes along the length of the flagellum (white arrow). B) The putative Ca²⁺ channel encoded by LmxM.33.0480, fused at its C-terminus to mNeonGreen, is restricted to the flagellum attachment zone (white arrow), a localized adhesion between the flagellar membrane and the flagellar pocket membrane near the base of the flagellum. C) A cNMP-PDE encoded by LmxM.08_29.2440, fused at its C-terminus to mNeonGreen, localizes to the flagellum with a concentration at the distal tip (white arrow) in many parasites. All images are of live parasites imaged in CyGel and represent superpositions of fluorescence and differential interference microscopy. Scale bars are 5 μm.

Fig. 3.

Import and export of iron and heme in Leishmania amazonensis. Lipid bilayers representing the plasma membrane are indicated at the top and bottom with the cytosol in between, and the mitochondrion is indicated in brown. LFR1 is an extracellularly oriented iron reductase that converts Fe³⁺ to Fe²⁺ at the parasite surface, generating the substrate for the iron permeases. Transporters for import (LIT1) or export (LIR1) of Fe²⁺ across the plasma membrane, for import of Fe²⁺ across the mitochondrial inner membrane (MIT1), and for import of heme across the plasma membrane (LHR1 and FLVCRb) are indicated as either ovals or a circle of different colors. Arrows indicate the direction of transport. Figure created with BioRender.com.