Leishmania infantum Enhances Migration of Macrophages via a Phosphoinositide 3-Kinase γ-Dependent Pathway

Abstract

Leishmania infantum (L. infantum) and Leishmania major (L. major) are phylogenetically related protozoan parasites that cause different pathologies in humans (visceral and cutaneous infections, respectively). Here, we report on how these obligatory intracellular pathogens differentially affect the migration of macrophages. Resorting to gap closure assays of infected murine bone marrow derived macrophages, we observed that L. infantum enhances the mobility of these cells. This is not the case of L. major, whose impact on macrophage migration is null. Resorting to kinase inhibition assays, we witnessed that chemical inhibition of phosphoinositide 3-kinase-γ (PI3Kγ) critically impairs cell mobility in all experimental conditions. Importantly, the blockade of tyrosine kinases with dasatinib also slows down naı̈ve and L. major-parasitized cells but not macrophages exposed to L. infantum. The dasatinib-resistant phenotype of L. infantum-infected macrophages aligns with the hypothesis that this parasite invokes a tyrosine kinase-independent pathway to increase the PI3Kγ activity of macrophages and enhance migration.

The cytosolic hyperoxidation-sensitive and -robust Leishmania peroxiredoxins cPRX1 and cPRX2 are both dispensable for parasite infectivity

“…BMDM, differentiated from monocytes of C57BL/6 mice following previously described protocols [ 50 ], were co-incubated with stationary phase promastigotes freshly recovered from spleens of infected mice at a macrophage:parasite ratio of 1:10. Three hours later, non-phagocytosed promastigotes were washed away and the time of the experiment set to zero.…”

Elucidating the Complex Interrelationship on Early Interactions betweenLeishmaniaand Macrophages

“…However, other authors have demonstrated that infection with Leishmania impairs the ability of macrophages to migrate [3,111]. In contrast with previous work, it has been shown that the modulation induced by Leishmania could depend on parasite species [116]. Thus, the modulation of macrophage migration induced by Leishmania, as well as impacts on parasite dissemination, remains unelucidated.…”

Redox-Responsive Nanocapsules for the Spatiotemporal Release of Miltefosine in Lysosome: Protection against Leishmania

“…The phagolysosomal maturation is broadly divided into four stages: (i) early phagosome stage having the molecular marker Rab-5, (ii) phagolysosomal fusion stage with molecular marker V−H+ ATPase, (iii) late phagosome stage characterized by molecular markers Cathepsin-D, Rab-7, and (iv) endosome recycling stage with molecular marker Rab-9 (Figure S5). 55,56 The attenuated phagolysosomal maturation in L. donovaniinfected macrophages may lead to an impaired acquisition of parasitic features. Concomitant with phagosome maturation is the progressive acidification of the phagosome lumen, which aids the killing and digestion of intracellular L. donovani in the lysosome.…”

“…The phagolysosomal maturation is broadly divided into four stages: (i) early phagosome stage having the molecular marker Rab-5, (ii) phagolysosomal fusion stage with molecular marker V–H+ ATPase, (iii) late phagosome stage characterized by molecular markers Cathepsin-D, Rab-7, and (iv) endosome recycling stage with molecular marker Rab-9 (Figure S5). , …”