Abstract
Leishmania, the causative agent of vector-borne diseases, known as leishmaniases, is an obligate intracellular parasite within mammalian hosts. The outcome of infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication. Understanding the strategies developed by the parasite to circumvent macrophage defense mechanisms and to survive within those cells help defining novel therapeutic approaches for leishmaniasis. We previously showed the formation of lipid droplets (LDs) in L. major infected macrophages. Here, we provide novel insights on the origin of the formed LDs by determining their cellular distribution and to what extent these high-energy sources are directed to the proximity of Leishmania parasites. We show that the ability of L. major to trigger macrophage LD accumulation is independent of parasite viability and uptake and can also be observed in non-infected cells through paracrine stimuli suggesting that LD formation is from cellular origin. The accumulation of LDs is demonstrated using confocal microscopy and live-cell imagin in parasite-free cytoplasmic region of the host cell, but also promptly recruited to the proximity of Leishmania parasites. Indeed LDs are observed inside parasitophorous vacuole and in parasite cytoplasm suggesting that Leishmania parasites besides producing their own LDs, may take advantage of these high energy sources. Otherwise, these LDs may help cells defending against parasitic infection. These metabolic changes, rising as common features during the last years, occur in host cells infected by a large number of pathogens and seem to play an important role in pathogenesis. Understanding how Leishmania parasites and different pathogens exploit this LD accumulation will help us define the common mechanism used by these different pathogens to manipulate and/or take advantage of this high-energy source.
Highlights
Leishmaniasis is an infectious disease caused by different species of the obligate intracellular parasite Leishmania
Our transcriptomic data show that among the set of genes exclusively up-regulated by live parasites (Fig 1 cluster 3), we found in particular those coding for PLA2 that catalyzes the hydrolysis of plasma membrane phospholipids to lysophospholipid and arachidonic acid the substrate of Ptgs2 and Ptges that catalyzes the production of prostaglandin E2
We evaluate the effect of L. major infection on lipid related genes transcripts and on cellular lipid droplets (LDs) formation and dynamics and provide novel insights into the origin of the formed LDs
Summary
Leishmaniasis is an infectious disease caused by different species of the obligate intracellular parasite Leishmania. It is an important cause of morbidity in developing countries with 1.3 million new cases and approximately 20 000 deaths each year [1]. Leishmania has evolved multiple strategies to invade and exploit many cells for its survival, including macrophages, the major target cells for parasite replication. These cells are in the first line of defense against pathogens and play a key role in the recruitment of other innate inflammatory cells. Understanding how the parasite acts to evade the macrophage defense mechanisms and survive within these cells may help defining novel therapeutic approaches to fight leishmaniasis
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